4,4-disubstitued-1,4-dihydro-2H-3,1-benzoxazin-2-ones useful as HIV reverse transcriptase inhibitors and intermediates and processes for making the same

ABSTRACT

The present invention relates to benzoxazinones of formula I: ##STR1## or stereoisomeric forms or mixtures, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of HIV reverse transcriptase, and to pharmaceutical compositions and diagnostic kits comprising the same, methods of using the same for treating viral infection or as an assay standard or reagent, and intermediates and processes for making the same.

This application claims the benefit of U.S. Provisional Application No. 60/027,137, filed Oct. 2, 1996, and U.S. Provisional Application No. 60/045,138, filed Apr. 30, 1997.

FIELD OF THE INVENTION

This invention relates generally to 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones which are useful as inhibitors of HIV reverse transcriptase, pharmaceutical compositions and diagnostic kits comprising the same, methods of using the same for treating viral infection or as assay standards or reagents, and intermediates and processes for making the same.

BACKGROUND OF THE INVENTION

Two distinct retroviruses, human immunodeficiency virus (HIV) type-1 (HIV-1) or type-2 (HIV-2), have been etiologically linked to the immunosuppressive disease, acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression which predisposes them to debilitating and ultimately fatal opportunistic infections.

The disease AIDS is the end result of an HIV-1 or HIV-2 virus following its own complex life cycle. The virion life cycle begins with the virion attaching itself to the host human T-4 lymphocyte immune cell through the bonding of a glycoprotein on the surface of the virion's protective coat with the CD4 glycoprotein on the lymphocyte cell. Once attached, the virion sheds its glycoprotein coat, penetrates into the membrane of the host cell, and uncoats its RNA. The virion enzyme, reverse transcriptase, directs the process of transcribing the RNA into single-stranded DNA. The viral RNA is degraded and a second DNA strand is created. The now double-stranded DNA is integrated into the human cell's genes and those genes are used for virus reproduction.

At this point, RNA polymerase transcribes the integrated DNA into viral RNA. The viral RNA is translated into the precursor gag-pol fusion polyprotein. The polyprotein is then cleaved by the HIV protease enzyme to yield the mature viral proteins. Thus, HIV protease is responsible for regulating a cascade of cleavage events that lead to the virus particle's maturing into a virus that is capable of full infectivity.

The typical human immune system response, killing the invading virion, is taxed because the virus infects and kills the immune system's T cells. In addition, viral reverse transcriptase, the enzyme used in making a new virion particle, is not very specific, and causes transcription mistakes that result in continually changed glycoproteins on the surface of the viral protective coat. This lack of specificity decreases the immune system's effectiveness because antibodies specifically produced against one glycoprotein may be useless against another, hence reducing the number of antibodies available to fight the virus. The virus continues to reproduce while the immune response system continues to weaken. Eventually, the HIV largely holds free reign over the body's immune system, allowing opportunistic infections to set in and without the administration of antiviral agents, immunomodulators, or both, death may result.

There are at least three critical points in the virus's life cycle which have been identified as possible targets for antiviral drugs: (1) the initial attachment of the virion to the T-4 lymphocyte or macrophage site, (2) the transcription of viral RNA to viral DNA (reverse transcriptase, RT), and (3) the processing of gag-pol protein by HIV protease.

Inhibition of the virus at the second critical point, the viral RNA to viral DNA transcription process, has provided a number of the current therapies used in treading AIDS. This transcription must occur for the virion to reproduce because the virion's genes are encoded in RNA and the host cell reads only DNA. By introducing drugs that block the reverse transcriptase from completing the formation of viral DNA, HIV-1 replication can be stopped.

A number of compounds that interfere with viral replication have been developed to treat AIDS. For example, nucleoside analogs, such as 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxycytidine (ddC), 2',3'-dideoxythymidinene (d4T), 2',3'-dideoxyinosine (ddI), and 2',3'-dideoxy-3'-thiacytidine (3TC) have been shown to be relatively effective in halting HIV replication at the reverse transcriptase (RT) stage.

Non-nucleoside HIV reverse transcriptase inhibitors have also been discovered. As an example, it has been found that certain benzoxazinones are useful in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and the treatment of AIDS. U.S. Pat. No. 5,519,021, the contents of which are hereby incorporated herein by reference, describe reverse transcriptase inhibitors which are benzoxazinones of the formula: ##STR2## wherein X is a halogen, Z may be O. However, benzoxazinones of this type are specifically excluded from the present invention.

In U.S. Pat. No. 5,519,021 one compound in particular, (-) 6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (NNRTI), shown below, ##STR3## has been found to be a potent and specific inhibitor of HIV-1 reverse transcriptase worthy of further study. NNRTI is described in Step D of Example 6 of the disclosure. Rat, monkey, and human microsomes treated with NNRTI, during investigation of the cytochrome P450 metabolism of NNRTI, produced a metabolite which was discovered to also be a potent inhibitor of HIV reverse transcriptase. This metabolite, its stereoisomer, stereoisomeric mixtures, and derivatives thereof are an embodiment of the present invention.

Even with the current success of reverse transcriptase inhibitors, it has been found that HIV patients can become resistant to a single inhibitor. Thus, it is desirable to develop additional inhibitors to further combat HIV infection.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novel reverse transcriptase inhibitors.

It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need thereof a therapeutically effective combination of (a) one of the compounds of the present invention and (b) one or more compounds selected form the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.

It is another object of the present invention to provide pharmaceutical compositions with reverse transcriptase inhibiting activity comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of the present invention to provide a method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of the present invention.

It is another object of the present invention to provide a kit or container containing at least one of the compounds of the present invention in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.

These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula (I): ##STR4## wherein A, W, X, Y, Z, R¹ and R² are defined below, stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt forms thereof, are effective reverse transcriptase inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

1! Thus, in a first embodiment, the present invention provides a novel compound of formula I: ##STR5## or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:

A is O or S;

W is N or CR³ ;

X is N or CR⁴ ;

Y is N or CR⁵ ;

Z is N or CR⁶ ;

provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

also, provided that if X is CR⁴ and R⁴ is F, Cl, Br, or I, then:

(a) at least one of W, Y, and Z is other than CH;

(b) R² is --OCHR⁷ R⁸ or --NHCHR⁷ R⁸ ;

(c) if R² is --C.tbd.C--R⁸, then R⁸ is C₃₋₇ cycloalkyl substituted with 1 R⁹ ; or

(d) any combination of (a), (b), and (c);

R¹ is selected from CF₃, CF₂ H, C₂ F₅, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R² is selected from --QCHR⁷ R⁸, --QCHR⁷ C.tbd.C--R⁸, --QCHR⁷ C═C--R⁸, --Q(CH₂)_(p) CHR⁷ R₈, --C.tbd.C--R⁸, --CH═CR⁷ R⁸, --(CH₂)_(p) CHR⁷ R⁸, --CHR⁷ C.tbd.C--R⁸, --CHR⁷ CH═CHR⁸, and CH═CHCHR⁷ R⁸ ;

provided that when R¹ is C₁₋₄ alkyl, then R² is --C.tbd.C--R⁸ ;

R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl;

R⁴ is selected from H, F, Cl, Br, I, Cl₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7a), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ;

alternatively, R³ and R⁴ together form --OCH₂ O--;

R⁵ is selected from H, F, Cl, Br, and I;

alternatively, R⁴ and R⁵ together form --OCH₂ O-- or a fused benzo ring;

R⁶ is selected from H, OH, C₁₋₃ alkoxy, --CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH₂ ;

R⁷ is selected from H and C₁₋₃ alkyl;

R^(7a) is selected from H and C₁₋₃ alkyl;

R^(7b) is C₁₋₃ alkyl;

R⁸ is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₆ alkenyl, C₃₋₇ cycloalkyl substituted with 0-2 R⁹, phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ;

R⁹ is selected from D, OH, C₁₋₃ alkoxy, C₁₋₃ alkyl, and F;

R¹⁰ is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ;

R¹¹ is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷ R^(7a), CHO, C(O)CH₃, C(O)NH₂ ;

Q is selected from O, S and NH; and,

p is selected from 0, 1, and 2.

2! In a preferred embodiment, the present invention provides a novel compound of formula I, wherein:

R¹ is selected from CF₃, CF₂ H, C₂ F₅, C₁₋₃ alkyl, C₃₋₅ cycloalkyl; and,

R⁸ is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₆ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰.

3! In a more preferred embodiment, the present invention provides a novel compound of formula I, wherein:

R¹ is selected from CF₃, CF₂ H, C₂ F₅, C₂ H₅, isopropyl, cyclopropyl;

R³ is selected from H, F, Cl, Br, I, OCH₃, CH₃ ;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7a), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form --OCH₂ O--;

R⁵ is selected from H, F;

R⁶ is selected from H, OH, OCH₃, --CN, F, CF₃, CH₃, and C(O)NH₂ ;

R⁷ is selected from H and CH₃ ;

R^(7a) is selected from H and CH₃ ;

R^(7b) is CH₃ ;

R⁸ is selected from H, C₁₋₄ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₄ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰ ;

R⁹ is selected from D, OH, OCH₃, CH₃, and F;

R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ; and,

p is selected from 1 and 2.

4! In an even more preferred embodiment, the present invention provides a novel compound of formula I, wherein:

A is O;

R¹ is selected from CF₃, CF₂ H, C₂ F₅ ;

R² is selected from --OCHR⁷ R⁸, --OCH₂ C.tbd.C--R⁸, --OCH₂ C═C--R⁸, --OCH₂ CHR⁷ R⁸, --C.tbd.C--R⁸, --CH═CR⁷ R⁸, --CH₂ CHR⁷ R⁸, --CH₂ C.tbd.C--R⁸, CHR⁷ CH═CHR⁸, and CH═CHCHR⁷ R⁸ ;

R³ is selected from H, F, Cl, Br, I;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C.tbd.CH, OCH₃, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), C(O)OR⁷, NR⁷ SO₂ R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form --OCH₂ O--; and,

R¹¹, is selected from OH, OCH₃, CN, F, Cl, NR⁷ R^(7a), C(O)CH₃, and C(O)NH₂.

5! In a further preferred embodiment, the compound of the present invention is selected from:

(±)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(-)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(±)-6-Chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(±)-4-Cyclopropylethynyl-4-isopropyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(±)-4-Isopropylethynyl-4-trifluoromethyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(±)-6-Acetyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(±)-5,6-Difluoro-4-(3-methyl)-1-buten-1-yl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(±)-4-Isopropylethynyl-4-trifluoromethyl-5,6-difluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(±)-4-Cyclopropylethynyl-6-chloro-4-trifluoromethyl-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(±)-6-Chloro-4-(2-methoxyethoxy)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(±)-6-Chloro-4-propylamino-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(±)-6-Chloro-4-(2-(furan-2-yl)ethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(±)-4-(1-Butynyl)-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(±)-4-(1'-Hydroxy)-cyclopropylethynyl-4-trifluoromethyl-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(±)-4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(±)-6-Chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; and,

(±)-4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one.

6! In a second embodiment, the present invention provides a novel compound of formula II: ##STR6## or a salt or stereoisomer thereof, wherein: A is O or S;

W is N or CR³ ;

X is N or CR⁴ ;

Y is N or CR⁵ ;

Z is N or CR⁶ ;

provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

R^(1a) is selected from CF₃, CF₂ H, C₂ F₅, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7a), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ;

alternatively, R³ and R⁴ together form --OCH₂ O--;

R⁵ is selected from H, F, Cl, Br, and I;

alternatively, R⁴ and R⁵ together form --OCH₂ O-- or a fused benzo ring;

R⁶ is selected from H, OH, C₁₋₃ alkoxy, --CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH₂ ;

R⁷ is selected from H and C₁₋₃ alkyl;

R^(7a) is selected from H and C₁₋₃ alkyl;

R^(7b) is C₁₋₃ alkyl;

R¹⁰ is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ;

R¹¹, is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷ R^(7a), CHO, C(O)CH₃, C(O)NH₂ ;

p is selected from 0, 1, and 2.

7! In a another preferred embodiment, the present invention provides a novel compound of formula II, wherein:

A is O; and,

R^(1a) is selected from CF₃, CF₂ H, C₂ F₅, C₁₋₃ alkyl, C₃₋₅ cycloalkyl.

8! In a more preferred embodiment, the present invention provides a novel compound of formula II, wherein:

R^(1a) is selected from CF₃, CF₂ H, C₂ F₅, C₂ H₅, isopropyl, cyclopropyl;

R³ is selected from H, F, Cl, Br, I, OCH₃, CH₃ ;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7a), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form --OCH₂ O--;

R⁵ is selected from H, F;

R⁶ is selected from H, OH, OCH₃, --CN, F, CF₃, CH₃, and C(O)NH₂ ;

R⁷ is selected from H and CH₃ ;

R^(7a) is selected from H and CH₃ ;

R^(7b) is CH₃ ;

R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ; and,

p is selected from 1 and 2.

9! In an even more preferred embodiment, the present invention provides a novel compound of formula II, wherein:

R^(1a) is selected from CF₃, CF₂ H, C₂ F₅ ;

R³ is selected from H, F, Cl, Br, I;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C.tbd.CH, OCH₃, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), C(O)OR⁷, NR⁷ SO₂ R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form --OCH₂ O--; and,

R¹¹, is selected from OH, OCH₃, CN, F, Cl, NR⁷ R^(7a), C(O)CH₃, and C (O) NH₂.

10! In a third embodiment, the present invention provides a novel process for making a compound of formula II: ##STR7## or a salt or stereoisomer thereof, comprising: (a) contacting a compound of formula III: ##STR8## or a suitable salt form thereof, with a carbonyl or thiocarbonyl delivering agent in the presence of a suitable solvent, wherein:

A is O or S;

W is N or CR³ ;

X is N or CR⁴ ;

Y is N or CR⁵ ;

Z is N or CR⁶ ;

provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

R^(1a) is selected from CF₃, CF₂ H, C₂ F₅, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7a), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ;

alternatively, R³ and R⁴ together form --OCH₂ O--;

R⁵ is selected from H, F, Cl, Br, and I;

alternatively, R⁴ and R⁵ together form --OCH₂ O-- or a fused benzo ring;

R⁶ is selected from H, OH, C₁₋₃ alkoxy, --CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH₂ ;

R⁷ is selected from H and C₁₋₃ alkyl;

R^(7a) is selected from H and C₁₋₃ alkyl;

R^(7b) is C₁₋₃ alkyl;

R¹⁰ is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ;

R¹¹ is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷ R^(7a), CHO, C(O)CH₃, C(O)NH₂ ;

Q is selected from O, S and NH; and,

p is selected from 0, 1, and 2.

11! In another preferred embodiment, in formulae II and III,

A is O;

R^(1a) is selected from CF₃, CF₂ H, C₂ F₅ ;

R³ is selected from H, F, Cl, Br, I;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C.tbd.CH, OCH₃, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), C(O)OR⁷, NR⁷ SO₂ R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form --OCH₂ O--; and,

R⁵ is selected from H, F;

R⁶ is selected from H, OH, OCH₃, --CN, F, CF₃, CH₃, and C(O)NH₂ ;

R⁷ is selected from H and CH₃ ;

R^(7a) is selected from H and CH₃ ;

R^(7b) is CH₃ ;

R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl , Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ;

R¹¹ is selected from OH, OCH₃, CN, F, Cl, NR⁷ R^(7a), C(O)CH₃, and C(O)NH₂ ; and,

p is selected from 1 and 2.

12! In another more preferred embodiment, the carbonyl delivering agent is selected from phosgene, carbonyldiimidazole, chloromethylcarbonate, chloroethylcarbonate, dimethylcarbonate, diethylcarbonate, and di-t-butylcarbonate.

13! In another even more preferred embodiment, the carbonyl delivering agent is phosgene and the solvent is toluene.

14! In another more preferred embodiment, in step (a) a base is present and is selected from trimethylamine, triethylamine, and N,N-disopropylethylamine.

15! In a fourth embodiment, the present invention provides of process for making a compound of formula Ia: ##STR9## or a stereoisomer or pharmaceutically acceptable salt form thereof, comprising:

(a) contacting a nucleophile, R^(2b), with a compound of formula II: ##STR10## or stereoisomer thereof in a suitable solvent, wherein: R^(2b) is selected from R⁸ R⁷ CH--OH, R⁸ R⁷ CH--OM, R⁸ R⁷ CHNH₂, R⁸ R⁷ CHNH--M, R⁸ --C.tbd.C--M, R⁷ R⁸ C═CH--M, R⁸ R⁷ CH(CH₂)_(p) --M, R⁸ CH═CHC(H) (R⁷)--M, R⁸ R⁷ CHCH═CH--M;

M is selected from Na, Li, Mg, Zn, Cu, Pd, Pt, Sn, Al, and B;

A is O or S;

W is N or CR³ ;

X is N or CR⁴ ;

Y is N or CR⁵ ;

Z is N or CR⁶ ;

provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

R^(1a) is selected from CF₃, CF₂ H, C₂ F₅, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R^(2a) is selected from --QCHR⁷ R⁸, --QCHR⁷ C.tbd.C--R⁸, --QCHR⁷ C═C--R⁸, --Q(CH₂)_(p) CHR⁷ R⁸, --C.tbd.C--R⁸, --CH═CR⁷ R⁸, --(CH₂)_(p) CHR⁷ R⁸, --CHR⁷ C.tbd.C--R⁸, --CHR⁷ CH═CHR⁸, and CH═CHCHR⁷ R⁸ ;

R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7a), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ;

alternatively, R³ and R⁴ together form --OCH₂ O--;

R⁵ is selected from H, F, Cl, Br, and I;

alternatively, R⁴ and R⁵ together form --OCH₂ O-- or a fused benzo ring;

R⁶ is selected from H, OH, C₁₋₃ alkoxy, --CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH₂ ;

R⁷ is selected from H and C₁₋₃ alkyl;

R^(7a) is selected from H and C₁₋₃ alkyl;

R^(7b) is C₁₋₃ alkyl;

R⁸ is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₆ alkenyl, C₃₋₇ cycloalkyl substituted with 0-2 R⁹, phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ;

R⁹ is selected from D, OH, C₁₋₃ alkoxy, C₁₋₃ alkyl, and F;

R¹⁰ is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I CN, NR⁷ R^(7a), and C(O)CH₃ ;

R¹¹ is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷ R^(7a), CHO, C(O)CH₃, C(O)NH₂ ;

Q is selected from O, S and NH; and,

p is selected from 0, 1, and 2

16! In another preferred embodiment, in formulae Ia and II,

A is O;

R^(1a) is selected from CF₃, CF₂ H, C₂ F₅ ;

R^(2a) is selected from --OCHR⁷ R⁸, --OCH₂ C.tbd.C--R⁸, --OCH₂ C═C--R⁸, --OCH₂ CHR⁷ R⁸, --C.tbd.C--R⁸, --CH═CR⁷ R⁸, --CH₂ CHR⁷ R⁸, --CH₂ C.tbd.C--R⁸, CHR⁷ CH═CHR⁸, and CH═CHCHR⁷ R⁸ ;

R³ is selected from H, F, Cl, Br, I;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C.tbd.CH, OCH₃, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), C(O)OR⁷, NR⁷ SO₂ R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form --OCH₂ O--; and,

R⁵ is selected from H, F;

R⁶ is selected from H, OH, OCH₃, --CN, F, CF₃, CH₃, and C(O)NH₂ ;

R⁷ is selected from H and CH₃ ;

R^(7a) is selected from H and CH₃ ;

R^(7b) is CH₃ ;

R⁸ is selected from H, C₁₋₄ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₄ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰ ;

R⁹ is selected from D, OH, OCH₃, CH₃, and F;

R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ;

R¹¹, is selected from OH, OCH₃, CN, F, Cl, NR⁷ R^(7a), C(O)CH₃, and C(O)NH₂ ; and,

p is selected from 1 and 2.

17! In another more preferred embodiment, in step (a), the compound of formula II is added to a solution containing the nucleophile.

18! In another more preferred embodiment, in step (a), R^(2b) is R⁸ --C.tbd.C--M; and M is selected from Li, Mg, and Zn.

19! In another even more preferred embodiment, in step (a), R⁸ --C.tbd.C--M is formed in situ by addition of a strong base to a solution containing R⁸ --C.tbd.C--H.

20! In another further preferred embodiment, in step (a), the strong base is selected from n-butyl lithium, s-butyl lithium, t-butyl lithium, phenyl lithium, and methyl lithium.

21! In another further preferred embodiment, the compound of formula Ia is: ##STR11## the compound of formula Ia is: ##STR12## the nucleophile R^(2b) is lithium cyclopropylacetylide; and, the solvent is THF.

22! In a fifth embodiment, the present invention provides a novel method of making a compound of formula IIIb: ##STR13## or stereoisomer or salt form thereof, comprising: (a) contacting a compound of formula IIIa: ##STR14## with R^(1a) --TMS and an anion, wherein: the anion is a fluoride or oxyanion and is selected from tetrabutylammonium fluoride, sodium fluoride, potassium fluoride, lithium fluoride, cesium fluoride, potassium tert-butoxide, sodium methoxide, sodium ethoxide and sodium trimethylsilanolate;

Pg is an amine protecting group;

W is N or CR³ ;

X is N or CR⁴ ;

Y is N or CR⁵ ;

Z is N or CR⁶ ;

provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

R^(1a) is selected from CF₃, CF₃ CF₂, and CF₃ CF₂ CF₂ ;

R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7a), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ;

alternatively, R³ and R⁴ together form --OCH₂ O--;

R⁵ is selected from H, F, Cl, Br, and I;

alternatively, R⁴ and R⁵ together form --OCH₂ O-- or a fused benzo ring;

R⁶ is selected from H, OH, C₁₋₃ alkoxy, --CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH₂ ;

R⁷ is selected from H and C₁₋₃ alkyl;

R^(7a) is selected from H and C₁₋₃ alkyl;

R^(7b) is C₁₋₃ alkyl;

R¹⁰ is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ;

R¹¹ is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷ R^(7a), CHO, C(O)CH₃, C(O)NH₂ ;

p is selected from 0, 1, and 2.

23! In another preferred embodiment, in formulae IIIa and IIIb,

the R^(1a) --TMS is trifluoromethyl trimethylsilane;

the anion is tetrabutylammonium fluoride;

Pg is trityl;

R^(1a) is CF₃ ;

R³ is selected from H, F, Cl, Br, I;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C.tbd.CH, OCH3, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), C(O)OR⁷, NR⁷ SO₂ R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form --OCH₂ O--; and,

R⁵ is selected from H, F;

R⁶ is selected from H, OH, OCH₃, --CN, F, CF₃, CH₃, and C(O)NH₂ ;

R⁷ is selected from H and CH₃ ;

R^(7a) is selected from H and CH₃ ;

R^(7b) is CH₃ ;

R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ;

R¹¹, is selected from OH, OCH₃, CN, F, Cl, NR⁷ R^(7a), C(O)CH₃, and C(O)NH₂ ; and,

p is selected from 1 and 2.

24! In another more preferred embodiment, the process further comprises:

(b) contacting a compound of formula IIIb with an oxidizing agent to form compound of formula IIIc: ##STR15##

25! In another even more preferred embodiment, the oxidizing agent is MnO₂.

In a fifth embodiment, the present invention provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or pharmaceutically acceptable salt form thereof.

In a sixth embodiment, the present invention provides a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of formula I or pharmaceutically acceptable salt form thereof.

In a seventh embodiment, the present invention provides a novel method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of:

(a) a compound of formula I; and,

(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.

In another preferred embodiment, the reverse transcriptase inhibitor is a nucleoside reverse transcriptase inhibitor.

In another more preferred embodiment, the nucleoside reverse transcriptase inhibitor is selected from AZT, 3TC, rescriptor, ddI, ddC, and d4T and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, VX-478, nelfinavir, KNI-272, CGP-61755, and U-103017.

In an even more preferred embodiment, the nucleoside reverse transcriptase inhibitor is selected from AZT, rescriptor, and 3TC and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, and nelfinavir.

In a still further preferred embodiment, the nucleoside reverse transcriptase inhibitor is AZT.

In another still further preferred embodiment, the protease inhibitor is indinavir.

In a eighth embodiment, the present invention provides a pharmaceutical kit useful for the treatment of HIV infection, which comprises a therapeutically effective amount of:

(a) a compound of formula I; and,

(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors, in one or more sterile containers.

In a ninth embodiment, the present invention provides a novel method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of formula I.

In a tenth embodiment, the present invention to provides a novel a kit or container comprising a compound of formula (I) in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.

DEFINITIONS

As used herein, the following terms and expressions have the indicated meanings. It will be appreciated that the compounds of the present invention contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.

The processes of the present invention are contemplated to be practiced on at least a multigram scale, kilogram scale, multikilogram scale, or industrial scale. Multigram scale, as used herein, is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, even more preferably at least 100 grams or more. Multikilogram scale, as used herein, is intended to mean the scale wherein more than one kilogram of at least one starting material is used. Industrial scale as used herein is intended to mean a scale which is other than a laboratory scale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.

The reactions of the synthetic methods claimed herein may be, as noted herein, carried out in the presence of a suitable base, said suitable base being any of a variety of bases, the presence of which in the reaction facilitates the synthesis of the desired product. Suitable bases may be selected by one of skill in the art of organic synthesis. Suitable bases include, but are not intended to be limited to, inorganic bases such as alkali metal, alkali earth metal, thallium, and ammonium hydroxides, alkoxides, phosphates, and carbonates, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, thallium hydroxide, thallium carbonate, tetra-n-butylammonium carbonate, and ammonium hydroxide. Suitable bases also include organic bases, including but not limited to aromatic and aliphatic amines, such as pyridine; trialkyl amines such as triethylamine, N,N-diisopropylethylamine, N,N-diethylcyclohexylamine, N,N-dimethylcyclohexylamine, N,N,N'-triethylenediamine, N,N-dimethyloctylamine; 1,5-diazabicyclo 4.3.0!non-5-ene (DBN); 1,4-diazabicyclo 2.2.2!octane (DABCO); 1,8-diazabicyclo 5.4.0!undec-7-ene (DBU); tetramethylethylenediamine (TMEDA); and substituted pyridines such as N,N-dimethylaminopyridine (DMAP), 4-pyrrolidinopyridine, 4-piperidinopyridine.

Suitable halogenated solvents include: carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane, 2-chloropropane, hexafluorobenzene, 1,2,4-trichlorobenzene, o-dichlorobenzene, chlorobenzene, or fluorobenzene.

Suitable ether solvents include, but are not intended to be limited to, dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, or t-butyl methyl ether.

Suitable protic solvents may include, by way of example and without limitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, anisole, benzyl alcohol, phenol, or glycerol.

Suitable aprotic solvents may include, by way of example and without limitation, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexamethylphosphoramide.

Suitable hydrocarbon solvents include, but are not intended to be limited to, benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or naphthalene.

As used herein, the term "amine protecting group" (or "N-protected") refers to any group known in the art of organic synthesis for the protection of amine groups. As used herein, the term "amine protecting group reagent" refers to any reagent known in the art of organic synthesis for the protection of amine groups which may be reacted with an amine to provide an amine protected with an amine protecting group. Such amine protecting groups include those listed in Greene and Wuts, "Protective Groups in Organic Synthesis" John Wiley & Sons, New York (1991) and "The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl (trityl) and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl.

Amine protecting groups may include, but are not limited to the following: 2,7-di-t-butyl- 9-(10,10-dioxo-10,10,10,10-tetrahydrothio-xanthyl)!methyloxycarbonyl; 2-trimethylsilylethyloxycarbonyl; 2-phenylethyloxycarbonyl; 1,1-dimethyl-2,2-dibromoethyloxycarbonyl; 1-methyl-1-(4-biphenylyl)ethyloxycarbonyl; benzyloxycarbonyl; p-nitrobenzyloxycarbonyl; 2-(p-toluenesulfonyl)ethyloxycarbonyl; m-chloro-p-acyloxybenzyloxycarbonyl; 5-benzyisoxazolylmethyloxycarbonyl; p-(dihydroxyboryl)benzyloxycarbonyl; m-nitrophenyloxycarbonyl; o-nitrobenzyloxycarbonyl; 3,5-dimethoxybenzyloxycarbonyl; 3,4-dimethoxy-6-nitrobenzyloxycarbonyl; N'-p-toluenesulfonylaminocarbonyl; t-amyloxycarbonyl; p-decyloxybenzyloxycarbonyl; diisopropylmethyloxycarbonyl; 2,2-dimethoxycarbonylvinyloxycarbonyl; di(2-pyridyl)methyloxycarbonyl; 2-furanylmethyloxycarbonyl; phthalimide; dithiasuccinimide; 2,5-dimethylpyrrole; benzyl; 5-dibenzylsuberyl; triphenylmethyl; benzylidene; diphenylmethylene; or methanesulfonamide.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example --C_(v) F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. "Cycloalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like. "Alkynyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like. "Halo" or "halogen" as used herein refers to fluoro, chloro, bromo and iodo. "Counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.

As used herein, "aryl" or "aromatic residue" is intended to mean an aromatic moiety containing the specified number of carbon atoms, such as phenyl or naphthyl. As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable 3- to 7- membered monocyclic or bicyclic which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term "heterocycle" or "heterocyclic system" is intended to mean a stable 5- to 6- membered monocyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 3 heteroatoms independently selected from the group consisting of N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term "aromatic heterocyclic system" is intended to mean a stable 5- to 6-membered monocyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 3 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, 2-pyrrolidonyl, 2H-pyrrolyl, 4-piperidonyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, and oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

As used herein, "HIV reverse transcriptase inhibitor" is intended to refer to both nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase (RT). Examples of nucleoside RT inhibitors include, but are not limited to, AZT, ddC, ddI, d4T, and 3TC. Examples of non-nucleoside RT inhibitors include, but are not limited to, rescriptor (delavirdine, Pharmacia and Upjohn), viviradine (Pharmacia and Upjohn U90152S), TIBO derivatives, BI-RG-587, nevirapine, L-697,661, LY 73497, and Ro 18,893 (Roche).

As used herein, "HIV protease inhibitor" is intended to refer to compounds which inhibit HIV protease. Examples include, but are not limited, saquinavir (Roche, Ro31-8959), ritonavir (Abbott, ABT-538), indinavir (Merck, MK-639), VX-478 (Vertex/Glaxo Wellcome), nelfinavir (Agouron, AG-1343), KNI-272 (Japan Energy), CGP-61755 (Ciba-Geigy), and U-103017 (Pharmacia and Upjohn). Additional examples include the cyclic protease inhibitors disclosed in WO93/07128, WO 94/19329, WO 94/22840, and PCT Application Number US96/03426.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

"Prodrugs" are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) or other formulas or compounds of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of the present invention, for example formula (I), are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein the hydroxy or amino group is bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl or free amino, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention, and the like.

"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are contempleted by the present invention.

"Substituted" is intended to indicate that one or more hydrogens on the atom indicated in the expression using "substituted" is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O) group, then 2 hydrogens on the atom are replaced.

"Therapeutically effective amount" is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.

SYNTHESIS

The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Each of the references cited below are hereby incorporated herein by reference. ##STR16##

Scheme 1 illustrates a method of making 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones starting from an appropriately substituted 2-aminobenzoic acid. The acid is converted to its N-methoxy-N-methyl amide derivative which can then be displaced to obtain the R¹ -substituted ketone. Subsequent addition of another metallic species provides the alcohol which is readily cyclized with phosgene or an equivalent thereof. ##STR17##

Scheme 2 describes a means of obtaining 4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-ones starting from an appropriately substituted aniline. After iodination, the trifluoromethyl group can be introduced using a strong base and ethyl trifluoroacetate. The second 4-substituent can then be added through anion attack on the ketone or using other means well known to those of skill in the art. Cyclization can be then be completed as in Scheme 1. ##STR18##

Because certain benzo-substituents are incompatible with the methods of Schemes 1 and 2, it may be necessary to protect these groups before forming the benzoxazinone. In Scheme 3 there is shown a means of obtaining carbonyl-substituted 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones. After iodination of an acetyl-aniline, the acetyl group is protected by means well known to those of skill in the art, such as using 1,3-propanedithiol. The same procedures as in Scheme 2 are used to arrive at the cyclized product. Deprotection of the ketone can then be achieved using HgCl₂ and HgO or other means well known to those of skill in the art. ##STR19##

A method for forming 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones, wherein R² is a vinyl or alkynyl group, is described in Scheme 4. Starting from an appropriately substituted ketone which can be obtained using the procedure of Scheme 1 or 2, an acetylide is added. The product can be deprotected and cyclized to obtain the alkynyl-substituted material. Alternatively, the vinyl compounds can be obtained by reduction of the alkyne with a reducing agent, such as LiAlH₄, deprotection by standard means, and cyclization. ##STR20##

Scheme 5 describes an alternate route to 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones from anilines, wherein the aniline is protected, ester addition is accomplished using a strong base and the amine protecting group is removed. The R² group can then be added, e.g. via an acetylide, followed by cyclization. ##STR21##

An intermediate useful in the preparation of the presently claimed compounds is 2-trifluoroacetylaniline. The starting 4-chloro-2-trifluoroacetylaniline can be made as shown in Scheme 2. Reduction and reoxidation removes the chloro group leaving the desired intermediate. ##STR22##

Scheme 7A describes a novel method of making 2-trifluoroacetylanilines as well as how these compounds can be further modified to make the presently claimed compounds. The protected aldehyde can be made from the N-methoxy-N-methyl amide of Scheme 1, by addition of a protecting group, preferably trityl, and reduction of the amide to the aldehyde. Other protecting groups known to those of skill in the art can be used in place of the shown trityl group. ##STR23##

Scheme 7B illustrates specific steps of Scheme 7A. Intermediate IIIb (R^(1a) is selected from CF₃, CF₃ CF₂, and CF₃ CF₂ CF₂) is useful for making some of the presently claimed compounds. Pg is an amine protecting group as defined previously, preferably trityl (triphenylmethyl). The protected or unprotected aminobenzaldehyde, preferably protected, is treated with a perfluoralkyl trimethylsilane, preferably trifluoromethyl trimethylsilane, followed by fluoride anion, preferably tetrabutylammonium fluoride. In the same fashion, CF₃ CF₂ TMS, CF₃ CF₂ CF₂ TMS can also be used to prepare the appropriately substituted ketones. Other sources of fluoride anion such as sodium fluoride, potassium fluoride, lithium fluoride, cesium fluoride as well as oxyanionic species such as potassium tert-butoxide, sodium methoxide, sodium ethoxide and sodium trimethylsilanolate can also be used. Aprotic solvents such as DMF and THF can be used, preferably THF. The amount of perfluoralkyl trimethylsilane used can be from about 1 to about 3 equivalents with an equivalent amount of fluoride anion or oxyanionic species. The reaction can be typically carried out at temperatures between about -20° C. to about 50° C., preferably about -10° to about 10° C., more preferably about 0° C.

Conversion of IIIb to IIIc can be achieved by using an oxidizing agent well known to one of skill in the art such as MnO₂, PDC, PCC, K₂ Cr₂ O₇, CrO₃, KMnO₄, BaMNO₄, Pb(OAc)₄, and RuO₄. A preferred oxidant is MnO₂. Such conversion can be performed in an aprotic solvent like THF, DMF, dichloromethane dichloroethane, or tetrachloroethane, preferably dichloromethane. ##STR24##

Scheme 8 illustrates a method of forming aza-4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones from an appropriately substituted amino-pyridine. Carbonyl addition to the pyridine can be accomplished using a strong base and an appropriate ketone. Addition of base can afford the cyclized product. ##STR25##

An additional means of making 4-alkynyl-1,4-dihydro-2H-3,1-benzoxazin-2-ones is shown in Scheme 9. The alkyne group is added to the keto-aniline via a Grignard type addition, followed by cyclization. The alkyne group of the product can then be modified to obtain the desired compound. ##STR26##

In addition to the methods of obtaining keto-anilines described in Schemes 1 and 2, nucleophilic opening of isatoic anhydrides can also be used as shown in Scheme 10. This reaction is accomplished by using an anionic nucleophile of the group R^(1a). See Mack et al, J. Heterocyclic Chem. 1987, 24, 1733-1739; Coppola et al, J. Org. Chem. 1976, 41(6), 825-831; Takimoto et al, Fukuoka Univ. Sci. Reports 1985, 15(1), 37-38; Kadin et al, Synthesis 1977, 500-501; Staiger et al, J. Org. Chem. 1959, 24, 1214-1219

It is preferred that the stoichiometry of the isatoic anhydride reagent to nucleophile is about 1.0 to 2.1 molar equivalents. The use of 1.0 eq. or more (e.g., 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0) of anion (or anion precursor) is preferred to force the conversion and improve the isolated yield. Preferably, the temperature used is from -20° to +35° C., with temperatures below 0° C. being more preferred and -20° C. being even more preferred. Reactions are run to about completion with time dependent upon inter alia nucleophile, solvent, and temperature. Preferably this nucleophilic addition is run in THF, but any aprotic solvent would be suitable. Reaction with the active nucleophilic anion is the only criterion for exclusion of a solvent. ##STR27##

An intermediate in this novel process is the chlorobenzoxazinone (II) which can be synthesized from the corresponding keto-aniline as shown in Scheme 11. The preparation of compounds of formula II works well with either the free base of the keto-aniline or its hydrochloride hydrate, though the free base is preferred due to its inherent reactivity. The carbonylation or thiocarbonylation reagent is selected from the group: phosgene (COCl₂), thiophosgene (CSCl₂), carbonyldiimidazole (CDI), chloromethylcarbonate, chloroethylcarbonate, dimethylcarbonate, diethylcarbonate, and di-t-butylcarbonate. Preferably, phosgene is used as the carbonylation reagent.

About 1, 2, 3, 4, or 5 equivalents of carbonylation or thiocarbonylation reagent are used, preferably from about 1 to about 2.5, even more preferably from about 1 to 2, and still further preferably about 1, 1.1, 1.2, 1.3, 1.4, or 1.5 equivalents. With volatile reagents like phosgene more than one equivalent can help the conversion and yield of the reaction but is not necessary to effect transformation.

Solvents such as toluene may be used. Additional non-reactive solvents, such as ethers (e.g., dimethyl ether and diethyl ether), hydrocarbons (e.g., hexane and cyclohexane) or other aromatic solvents (e.g., benzene, anisole, or quinoline) can also be used. Solvents with boiling points around that of toluene or higher are preferred. Use of such solvents allows heat to be applied to the reaction to promote the cyclization. When the preferred carbonylation reagent, phosgene is use, heat helps drive off the HCl generated and promote the closure reaction. When toluene is used, it is preferred to run the reaction near toluene's boiling point. However, one of ordinary skill in the art would recognize that too high of a temperature may decompose the product. In addition, too low of a temperature may cause an undesirably slow reaction. Reaction progress may be determined by the decoloration of the reaction mixture (indicating consumption of starting material) and confirmation of completeness by proton NMR. The reaction may be catalyzed by the addition of an acid scavenger such as an amine base (e.g., triethylamine or Hunigs base) or an inorganic base (e.g., sodium carbonate or potassium). ##STR28##

Scheme 12 describes routes to a variety of R² -substituted compounds of formula Ia by reacting a nucleophile (R^(2b)) with a compound of formula II (preferably R^(1a) is CF₃). This displacement reaction is quite versatile and a large range of nucleophiles can be used. Preferably the nucleophile is an amine (e.g., R⁸ R⁷ CHNH) or a metallic species selected from R⁸ R⁷ CH--OM, R⁸ R⁷ CH--SM, R⁸ R⁷ CHNH--M, R⁸ --C.tbd.C--M, R⁷ R⁸ C═CH--M, R⁸ R⁷ CH(CH₂)_(p) --M, R⁸ CH═CHC(H)(R⁷)M, and R⁸ R⁷ CHCH═CH--M. In addition, R⁸ R⁷ CH--OH and its thiol analog, R⁸ R⁷ CH--SH, can be used without formation of their corresponding anions. The metallic moiety, M, is selected from the group Na, Li, Zn, Mg, Cu. Pd. Pt. Sn, Al, and B, preferably Li, Mg, or Zn.

If an metallic nucleophile is used, it may be made in situ by methods known to those of skill in the art or formed by methods known to those of skill in the art and then added to a solution. In either case, it is preferred that: the compound of formula II is added to a solution containing the nucleophile.

Preferably, the nucleophile is an acetylide (i.e., R⁸ --C.tbd.C--M) with Li, Mg, or Zn as the counterion. Acetylides are well known in the art. Preferably, R⁸ --C.tbd.C--M is formed in situ by addition of a strong base to a solution containing R⁸ --C.tbd.C--H. Strong bases are well known to those of skill in the art and include, but are not limited to n-butyl lithium, s-butyl lithium, t-butyl lithium, phenyl lithium, and methyl lithium. Preferably, the strong base is n-butyl lithium. The acetylide may also be made in situ by addition of a strong base to a dihalo-olefin (e.g., Br₂ C═CHR⁸).

In the nucleophilic addition reactions the stochiometery is preferably about one equivalent of benzoxazinone to about 1.0 to 2.5 equivalents of nucleophile (e.g., 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5). More preferable about 1.8 to 2.4 equivalents are used. Even more preferably, 2.1 equivalents of nucleophile are used. It is noted that less than one equivalent may be used, but care must be taken as N--H deprotonation reaction may compete with nucleophilic addition. It is preferable to run the additions from -40° to 0° C., more preferably about -20° C. The solvent used is preferably THF, but any aprotic solvent, such as dimethyl ether, diethyl ether, benzene, or toluene, should be suitable. Non-reaction with the nucleophile, specifically the nucleophilic anion, is the only criterion for exclusion of a solvent.

An additional example of the utility of the final nucleophilic addition step of the present invention is shown in Scheme 13. ##STR29##

A preferred example of the present process is shown in Scheme 14. ##STR30##

In Scheme 14, the preferred temperature of the carbonylation reaction is from about 104° to about 110° C. and the preferred temperature of the acetylide addition is about -20° C.

One enantiomer of a compound of Formula I may display superior activity compared with the other. Thus, both of the following stereochemistries are considered to be a part of the present invention. ##STR31## When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g. Andrew S. Thompson, et al, Tet. lett. 1995, 36, 8937-8940.

Another method of forming a compound wherein Z is C(OH) involves incubating NNRTI, or a derivative thereof, in microsomes obtained from male rats, male rhesus monkeys or humans, preferably male rats. In addition, it is preferable to orally dose the male rats with NNRTI prior to collection of their livers and microsomal isolation. This procedure will be described in the following Example section.

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

Abbreviations used in the Examples are defined as follows: "° C." for degrees Celsius, "d" for doublet, "dd" for doublet of doublets, "eq" for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, "mL" for milliliter or milliliters, "H" for hydrogen or hydrogens, "hr" for hour or hours, "m" for multiplet, "M" for molar, "min" for minute or minutes, "MHz" for megahertz, "MS" for mass spectroscopy, "nmr" or "NMR" for nuclear magnetic resonance spectroscopy, "t" for triplet, "TLC" for thin layer chromatography, "EDAC" for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, "DIPEA" for diisopropylethylamine, "TBAF" for tetrabutylammonium fluoride, "LAH" for lithium aluminium hydride, and "TEA" for triethylamine.

Example 1 ##STR32## Preparation of (±)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 4'-Chloro-2'-methoxy-2,2-dimethylpropionanilide

A stirred solution of 22.6 g (100 mmol) of stannous chloride dihydrate in 40 mL of absolute ethanol was heated to reflux and treated with 3.75 g (20 mmol) of 5-chloro-2-nitroanisole in 20 mL of 1:1 ethanol-tetrahydrofuran over 3 min. Stirring at reflux for an additional 10 minutes gave a clear solution which was then cooled to 0° C. The mixture was treated with aqueous Na₂ CO₃ until a pH of 8-9 was reached. The colloidal suspension was extracted twice with ethyl acetate, and the combined organic extracts were washed with saturated NaHCO₃ then brine. The solution was dried (MgSO₄) and concentrated under reduced pressure. The crude oil was dissolved in 40 mL of CH₂ Cl₂ and cooled to 0° C. The solution was treated with 4.2 mL (30 mmol) of triethylamine followed by 2.8 mL (23 mmol) of pivaloyl chloride. After stirring 2 h at 0° C. the mixture was quenched with 0.5N HCl, and the phases were separated. The aqueous phase was extracted with 100 mL of 1:1 ether-hexanes, and the combined organic extracts were washed sequentially with 0.1N HCl, dilute K₂ CO₃, water, and brine. The solution was dried (MgSO₄) and concentrated under reduced pressure to give 4.68 g (97%) of 4'-chloro-2'-methoxy-2,2-dimethylpropionanilide as an tan solid, mp 66°-69° C. ¹ H NMR (300 MHz, CDCl₃) δ8.36(d, 1H, J=8.8 Hz); 8.03(br. s, 1H); 6.94(dd, 1H, J=8.8, 2.2 Hz); 6.86(d, 1H, J=2.2 Hz); 3.90(s, 3H); 1.32(s, 9H). High resolution mass spec: calculated for C₁₂ H₁₇ NO₂ Cl(M+H)⁺ : 242.0948, found: 242.0943. Analysis calculated for C₁₂ H₁₆ NO₂ Cl: C, 59.63; H, 6.67; N, 5.79; Cl, 14.67. Found: C, 59.73; H, 6.67; N, 5.57; Cl, 14.42.

Part B: Preparation of 2'-Amino-5'-chloro-3'-methoxy-2,2,2-trifluoroacetophenone

To a stirred, cooled (-20° C.) solution of 12.1 g (50 mmol) of 4'-chloro-2'-methoxy-2,2-dimethylpropionanilide in 150 mL of THF was added 87 mL (115 mmol) of 1.3M s-BuLi in cyclohexane over 15 min. The dark solution was warmed to 0° C. and stirred for 1.2 h. The solution was re-cooled to -20° C. and treated with 14.3 mL (120 mmol) of ethyl trifluoroacetate over 5 min. The reaction was warmed to 0° C., stirred 15 min., and quenched with saturated aqueous NaHCO₃. The mixture was extracted with hexanes and then with ether, and the combined organic extracts were washed sequentially with 0.5N HCl, water, and brine. The solution was dried (MgSO₄) and concentrated under reduced pressure to give a dark oil. The crude amide was dissolved in 20 mL of 1,2-dimethoxyethane and treated with 100 mL of 6N aqueous HCl. The mixture was stirred at reflux for 2 h, cooled to 0° C., and brought to pH 9 with K₂ CO₃. The mixture was extracted twice with ether, and the combined organic extracts were washed with brine, dried (MgSO₄), and concentrated under reduced pressure to give an oily solid. This crude product was recrystallized from hexanes and a minimal amount of ethyl acetate to give 7.75 g (61%) of 2'-amino-5'-chloro-3'-methoxy-2,2,2-trifluoroacetophenone as yellow needles, mp 124.5°-125.5° C. ¹ H NMR (300 MHz, CDCl₃) δ7.32-7.35(m, 1H); 6.87(br. s, 2H); 6.84(d, 1H, J=1.8 Hz); 3.92(s, 3H). High resolution mass spec: calculated for C₉ H₈ NO₂ ClF₃ (M+H)⁺ : 254.0196, found: 254.0194. Analysis calculated for C₉ H₇ NO₂ ClF₃ : C, 42.62; H, 2.78; N, 5.52; Cl, 13.98. Found: C, 42.52; H, 3.04; N, 5.40; Cl, 13.74.

Part C: Preparation of 2'-Amino-5'-chloro-3'-hydroxy-2,2,2-trifluoroacetophenone

To a stirred, cooled (0° C.) solution of 31.2 g (123 mmol) of 2'-amino-5'-chloro-3'-methoxy-2,2,2-trifluoroacetophenone in 150 mL of CH₂ Cl₂ was added 550 mL (550 mmol) of 1M BBr₃ in CH₂ Cl₂ over 20 min. The dark solution was stirred 17 h at ambient temperature, re-cooled to 0° C., and fitted with a pressure-equalizing dropping addition funnel and a Claisen adapter connected by rubber tubing to a large water scrubber. The reaction was carefully quenched by dropwise addition of aqueous Na₂ CO₃ until a pH of 7-8 was reached. The phases were separated, and the aqueous phase was extracted with 1 liter of 1:1 ether-hexanes. The combined organic phases were washed with water then brine, dried (MgSO₄), and concentrated under reduced pressure to afford 30.1 g (100%) of 2'-amino-5'-chloro-3'-hydroxy-2,2,2-trifluoroacetophenone as a chalky brown solid, mp 120°-122° C. ¹ H NMR (300 MHz, CDCl₃) δ7.33-7.36(m, 1H); 6.88(d, 1H, J=1.8 Hz); 6.75(br. s, 2H); 5.78(br. s, 1H). High resolution mass spec: calculated for C₈ H₆ NO₂ ClF₃ (M+H)⁺ : 240.0039, found: 240.0029.

Part D: Preparation of 2'-Amino-5'-chloro-3'-(t-butyldimethylsilyloxy)-2,2,2-trifluoroacetophenone

To a stirred, cooled (0° C.) solution of 29.3 g (122 mmol) of 2'-amino-5'-chloro-3'-hydroxy-2,2,2-trifluoroacetophenone in 280 mL of DMF was added 23.8 g (350 mmol) of imidazole followed by 66 g (250 mmol) of t-butyldimethylsilyl trifluoromethanesulfonate over 10 min. The reaction was stirred 5 h at 0° C. and diluted with 800 mL of 1:1 ether-hexanes. The solution was washed twice with water and once with brine, dried (MgSO₄) and concentrated under reduced pressure to give a dark oil. The crude product was rapidly passed through an 800 g plug of silica gel (elution with hexanes followed by 6:1 hexanes-ether) to afford, after evaporation of solvent, 42.5 g (98%) of 2'-amino-5'-chloro-3'-(t-butyldimethylsilyloxy)-2,2,2-trifluoroacetophenone as a yellow oil. The product solidified after extended evacuation at 0.01 torr to give a yellow solid, mp 45°-46.5° C. ¹ H NMR (300 MHz, CDCl₃) δ7.34-7.36(m, 1H); 6.85(d, 1H, J=2.2 Hz); 6.7-6.8(br. s, 2H); 1.03(s, 9H); 0.30(s, 6H). High resolution mass spec: calculated for C₁₄ H₂₀ NO₂ ClF₃ Si(M+H)⁺ : 354.0904, found: 354.0900. Analysis calculated for C₁₄ H₁₉ NO2ClF₃ Si: C, 47.52; H, 5.41; N, 3.97; Cl, 10.02. Found: C, 47.71; H, 5.36; N, 3.87; Cl, 10.02.

Part E: Preparation of (±)-2-(2-Amino-5-chloro-3-(t-butyldimethylsilyloxy) phenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol

To a stirred, cooled (0° C.) solution of 31.8 mL (300 mmol) of 5-chloro-1-pentyne in 250 mL of THF was added 252 mL (630 mmol) of 2.5M n-BuLi in hexanes over 20 min. Over the course of the addition the internal temperature had warmed to ambient temperature, and the mixture was stirred at this temperature for 40 min. The reaction was cooled to -20° C. and treated with a solution of 32.7 g (97.4 mmol) of 2'-amino-5'-chloro-3'-(t-butyldimethylsilyloxy)-2,2,2-trifluoroacetophenone in 50 mL of THF over 10 min. The dark solution was stirred an additional 30 min. and the cold bath was removed. The reaction was stirred 5 min and poured into 800 mL of 0° C. 1N citric acid with rapid stirring. The mixture was extracted twice with ether, and the combined organic extracts were washed with water then brine, dried (MgSO₄), and concentrated under reduced pressure. Chromatography on silica gel (elution with hexanes then 3:1 hexanes-ether) afforded 28.8 g (70%) of (±)-2-(2-amino-5-chloro-3-(t-butyldimethylsilyloxy)phenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol as an off-white solid, mp 125°-126° C. ¹ H NMR (300 MHz, CDCl₃) δ7.22(d, 1H, J=2.2 Hz); 6.76(d, 1H, J=2.2 Hz); 4.86(br. s, 1H); 4.39(br. s, 2H); 1.32-1.43(m, 1H); 1.02(s, 9H); 0.79-0.92(m, 4H); 0.27(s, 3H); 0.26(s, 3H). High resolution mass spec: calculated for C₁₉ H₂₆ NO₂ ClF₃ Si(M+H)⁺ : 420.1373, found: 420.1363.

Part F: Preparation of (±)-6-Chloro-4-cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a stirred, cooled (-25° C.) solution of 28.8 g(68.6 mmol) (±)-2-(2-amino-5-chloro-3-(t-butyldimethylsilyloxy)phenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol in 600 mL of toluene was added 36 mL (206 mmol) of N, N-diisopropylethylamine followed by 38.9 mL (75 mmol) of a 1.93M solution of phosgene in toluene over 20 min. The solution was stirred an additional 20 min. at -25° C. after which time it was warmed to -5° C. and quenched with water. The mixture was washed with 100 mL of 1N aqueous HCl then brine, dried (MgSO₄), and concentrated under reduced pressure to afford a tan solid. The crude product was dissolved in 200 mL of THF, cooled to 0° C., and treated with 40 mL of 1M tetra-(n-butyl)ammonium fluoride in THF over 5 min. The solution was diluted with 200 mL of ether and washed sequentially with 1M aqueous citric acid, water, and brine. The solution was dried (MgSO₄), concentrated under reduced pressure, and chromatographed on silica gel. Elution with 1:3 ether-hexanes then 1:1 ether-hexanes afforded, after concentration under reduced pressure, 21.4 g (94%) of (±)-6-chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one as an off-white solid. ¹ H NMR (300 MHz, CDCl₃) δ8.46(br s, 1H); 7.01-7.07(m, 2H); 1.33-1.43(m, 1H); 0.81-0.97(m, 4H). High resolution mass spec: calculated for C₁₄ H₁₀ NO₃ ClF₃ (M+H)⁺ : 332.0301, found: 332.0283.

Example 2 ##STR33## Preparation of (-)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

Chromatography of 22 g of racemic 6-chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (I) on a Chiralpak AD-7.5 cm I.D.×30 gm column using 20% methanol-80% carbon dioxide as the mobile phase at a flow rate of 120 mL/min. gave two fractions. The faster-eluting fraction was concentrated and recrystallized from hexanes and a minimal amount of ethyl acetate to afford 5 g of the title compound as a white solid, mp 170°-172° C. ¹ H NMR (300 MHz, CDCl₃) δ8.46(br s, 1H); 7.01-7.07(m, 2H); 1.33-1.43(m, 1H); 0.81-0.97(m, 4H). α!Na_(d) (25° C.)=-32°, c=0.28. Analysis calculated for C₁₄ H₉ NO₃ ClF₃ : C, 50.70; H, 2.75; N, 4.22; Cl, 10.69. Found: C, 50.74; H, 2.86; N, 4.26; Cl, 10.77.

Example 3 Preparation of (-) 6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one by Rat Hepatic Microsomal Fractions

Incubation of (-) 6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (NNRTI) with hepatic microsomes from rats previously treated with NNRTI and cofactors required to support cytochromes P450 oxidative metabolism resulted in the formation of one major metabolite separable from NNRTI by reverse phase high performance liquid chromatography (HPLC). Incubations were conducted for 2 hours at 37° C. in a physiological buffer. After precipitating the protein with acetonitrile, the supernatants were dried under nitrogen and reconstituted in a mixture of 55:45 (v/v) acetonitrile:0.01% aqueous formic acid (pH 3.5) and injected onto the HPLC system. The column effluent was monitored at 247 nm. The single peak observed to elute at approximately 4 minutes was collected and combined from multiple injections. Final purification was accomplished using the same HPLC system and a linear gradient developed over 15 minutes starting with solvent A (50:50 (v/v) methanol:0.01% aquesous formic acid, pH 3.5) and increasing the proportion of solvent B (80:20 v/v methanol:0.01% aqueous formic acid pH 3.5), then holding solvent B constant for 5 minutes before re-equilibration with solvent A. The single, sharp peak eluting at approximately 16.5 minutes was collected and dried under vacuum.

The purified metabolite described above was dissolved in 0.2 mL of methanol-d4 and placed in a 3 mm NMR tube. The proton NMR spectrum was acquired using a 30 degree pulse, a 4 second acquisition time and a 2 second relaxation delay during which the residual water signal was suppressed by selective irradiation. The spectrum was referenced to solvent at 3.30 ppm.

Example 4 ##STR34## Preparation of (±)-6-Chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 4'-Chloro-2'-fluoro-2,2-dimethylpropionanilide

To a stirred, cooled (0° C.) solution of 3.64 g (25.0 mmol) of 4-chloro-2-fluoroaniline and 4.2 mL (30 mmol) of triethylamine in 50 mL of THF was added 4.18 mL (26 mmol) of pivaloyl chloride. After stirring for 10 min. at 0° C. the mixture was warmed to ambient temperature and poured into 0.5N HCl. The mixture was extracted with 100 mL of ether, and the organic extract was washed sequentially with NaHCO₃ and brine. The solution was dried (MgSO₄), concentrated under reduced pressure, and chromatographed on silica gel (elution with 3:1 hexanes-ether) to give, after removal of solvent, 5.2 g (92%) of 4'-chloro-2'-fluoro-2,2-dimethylpropionanilide as a pale pink solid (IX), mp 70.5°-71° C. ¹ H NMR (300 MHz , CDCl₃) δ8.36(t, 1H, J=8.4 Hz); 7.57(br. s, 1H); 7.10-7.17(m, 2H); 1.30(s, 9H). ¹⁹ F NMR (282 MHz , CDCl₃) δ-129.8. High resolution mass spec: calculated for C₁₁ H₁₄ NOClF(M+H)⁺ : 230.0748, found: 230.0760.

Part B: Preparation of 2'-(Trimethylacetamido)-5'-chloro-3'-fluoro-2,2,2-trifluoroacetophenone

To a stirred, cooled (-50° C.) solution of 0.92 g (4.0 mmol) of 4'-chloro-2'-fluoro-2,2-dimethylpropionanilide in 10 mL of THF was added 2.5 mL (4.2 mmol) of 1.7M t-BuLi in pentane over 5 min. The solution was stirred for 5 min. and treated with 1.0 mL (8.4 mmol) of ethyl trifluoroacetate over 2 min. The reaction was warmed to ambient temperature, stirred 15 min., and quenched with 1N aqueous citric acid. The mixture was extracted with ether, and the organic extract was washed sequentially with water then brine. The solution was dried(MgSO₄) and concentrated under reduced pressure to give an oil. The crude amide was chromatographed on silica gel (elution with 3:1 hexanes-ether followed by 1:1 hexanes-ether) to give 570 mg (43%) of 2'-(trimethylacetamido)-5'-chloro-3'-fluoro-2,2,2-trifluoroacetophenone as an off-white solid. ¹ H NMR(300 MHz, CDCl₃) δ8.68(s, 1H); 7.45-7.47(m, 1H); 7.08(dd, 1H, J=9.5, 2.6 Hz); 1.3(s, 9H). High resolution mass spec: calculated for C₁₃ H₁₃ NO₂ ClF₄ (M+H)⁺ : 326.0571, found: 326.0579.

Part C: Preparation of 2'-Amino-5'-chloro-3'-fluoro-2,2,2-trifluoroacetophenone

A stirred solution of 0.35 g (1.07 mmol) of 2'-(trimethylacetamido)-5'-chloro-3'-fluoro-2,2,2-trifluoroacetophenone in 3 mL of 1,2-dimethoxyethane and treated with 24 mL of 6N aq. HCl. The mixture was stirred at reflux for 2 h, cooled to RT, and brought to pH 9 with K₂ CO₃. The mixture was extracted twice with ether and the combined organic extracts were washed with brine, dried (MgSO₄), and concentrated under reduced pressure to give 240 mg (92%) of 2'-amino-5'-chloro-3'-fluoro-2,2,2-trifluoroacetophenone as an oily orange solid. ¹ H NMR (300 MHz , CDCl₃) δ7.54(m, 1H); 7.25(dd, 1H, J=10.6, 2.2 Hz); 6.40-6.60(br. s, 2H). High resolution mass spec: calculated for C₈ H₄ NOClF₄ (M⁺): 240.9918, found: 240.9914. ¹⁹ F NMR (282 MHz , CDCl₃) δ-132.7(s, 1F), -70.6(s, 3F).

Part D: Preparation of (±)-2-Amino-5-chloro-3-fluoro-α-(cyclopropylethynyl)-α-(trifluoromethyl)benzyl alcohol

To a stirred, cooled (0° C.) solution of 2.0 mL (7.0 mmol) of 3.5M cyclopropylacetylene in toluene was added 2 mL of THF followed by 2.8 mL (7.0 mmol) of 2.5M n-BuLi in hexanes over 2 min. The solution was stirred 5 min. at 0° C., warmed to RT, and stirred a further 20 min. The reaction was cooled to 0° C. and treated with a solution of 300 mg (1.24 mmol) of 2'-amino-5'-chloro-3'-fluoro-2,2,2-trifluoroacetophenone in 3mL of THF over 2 min. The solution was stirred an additional 10 min. and the cold bath was removed. The reaction was stirred 5 min and poured into 0.5N citric acid. The mixture was extracted with ether, and the organic extract was washed with water then brine, dried (MgSO₄), and concentrated under reduced pressure. Chromatography on silica gel (elution with hexanes then 3:1 hexanes-ether) afforded 185 mg (49%) of (±)-2-amino-5-chloro-3-fluoro-α-(cyclopropylethynyl)-α-(trifluoromethyl)benzyl alcohol as an off-white solid, mp 131°-135° C. ¹ H NMR (300 MHz, CDCl₃) δ7.34-7.36(m, 1H); 7.04(dd, 1H, J=10.4, 2.4 Hz); 4.58(br. s, 2H); 3.82(br. s, 1H); 1.35-1.44(m, 1H); 0.80-0.99(m, 4H). ¹⁹ F NMR (282 MHz, CDCl₃) δ-131.5(s, 1F), -80.5(s, 3F). High resolution mass spec: calculated for C₁₃ H11NOClF₄ (M+H)⁺ : 308.0470, found: 308.0465.

Part E: Preparation of (±)-6-Chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a stirred, cooled (-25° C.) solution of 144 mg (0.47 mmol) of (±)-2-amino-5-chloro-3-fluoro-α-(cyclopropylethynyl)-α-(trifluoromethyl)benzyl alcohol in 6 mL of toluene was added 0.28 mL (2.0 mmol) of triethylamine followed by 0.62 mL(1.2 mmol) of a 1.93M solution of phosgene in toluene over 3 min. The solution was stirred an additional 30 min. at -25° C. after which time it was warmed to ambient temperature and quenched with 0.5N aq. citric acid. The mixture was extracted once with ether and once with ethyl acetate, and the combined organic extracts were washed sequentially with sat'd aq. NaHCO₃, water, and brine. The solution was dried (MgSO₄), and concentrated under reduced pressure to afford a tan solid. The crude product was chromatographed on silica gel(elution with 3:1 hexanes-ether) to afford, after concentration, 90 mg (58%) of (±)-6-chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one as an off-white solid. ¹ H NMR (300 MHz , CDCl₃) δ7.65(br s, 1H); 7.32-7.34(m, 1H); 7.22(d, 1H, J=2.2 Hz); 1.36-1.43(m, 1H); 0.82-0.98(m, 4H). ¹⁹ F NMR (282 MHz, CDCl₃) δ-132.5(s, 1F), -81.1(s, 3F). High resolution mass spec: calculated for C₁₄ H₉ NO2ClF₄ (M+H)⁺ : 334.0258, found: 334.0244.

Example 5 Preparation of (±)-4-Cyclopropylethynyl-4-isopropyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 2-Amino-5-methylbenzoyl N-methoxy-methylamide.

To a solution of 2-amino-5-methylbenzoic acid (7.6 g, 50.3 mmol) and N,O-dimethylhydroxylamine hydrochloride (12.5 g, 60.4 mmol) in acetonitrile (80 mL) were added triethylamine (15.8 mL, 60.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.3 g, 55.3 mmol) and the mixture was stirred at room temperature for 5 hours. At the end of the stirring, methylene chloride (200 mL) was added and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give a yellow syrupy residue. It was purified by column chromatography on silica gel with elution by 15:85 ethyl acetate-hexane to give pure 2-amino-5-methylbenzoyl N-methoxy-methylamide.

Part B: Preparation of 2-Amino-5-methylphenylisopropylketone.

To a solution of 2-amino-5-methylbenzoyl N-methoxy-methylamide (472.6 mg, 2.4 mmol) in dry THF (3 mL) at -20° C. were added diisopropylethylamine (0.84 mL, 4.8 mmol) and chlorotrimethylsilane (0.61 mL, 4.8 mmol) dropwise and the mixture was stirred for 1 hour at -20°˜5° C. It was then cooled to -20° C. again and was added 2M-isopropyl magnesium chloride in THF (4.8 mL, 9.6 mmol) dropwise. The mixture was stirred for 1.5 hours at -20°˜10° C. After cooling to 0° C. was added saturated ammonium chloride and extracted with EtOAc. The organic layer was washed with 1N-HCl, water, saturated sodium bicarbonate and water, and dried over anhydrous sodium sulfate. It was evaporated in vacuo to give an oily residue. Column chromatography on silica gel with elution by 1:9 ethyl acetate-hexane affored pure 2-amino-5-methylphenylisopropylketone (201 mg) as an oil.

Part C: Preparation of 2-Amino-5-methyl-α-cyclopropylethynyl-α-isopropyl-benzyl alcohol.

To a solution of cyclopropylacetylene (105 mg, 1.59 mmol) in THF (3 mL) at -20° C. was added 1.6M-nBuLi in hexane (0.96 mL, 1.54 mmol) dropwise and the mixture was stirred at the same temperature for 0.5 hours. Then a solution of 2-amino-5-methylphenylisopropylketone (94.5 mg, 0.53 mmol) in THF (3 mL) was added and the mixture was stirred for 5 hours at -20°˜20° C. The reaction was quenched with saturated NH₄ Cl and the product was extraxted with ethyl acetate. After washing with brine, the extract was dried over anhydrous sodium sulfate and evaporated to give the crude amino-alcohol as an oil.

Part D: Preparation of 4-Cyclopropylethynyl-4-isopropyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

To a solution of the crude amino-alcohol (0.53 mmol) in dry toluene (5 mL) at -20° C. were added diisopropylethylamine (0.29 mL, 1.89 mmol) and 0.31 mL of 20% solution of phosgene in toluene dropwise and the mixture was stirred for 1 hour at -20°˜0° C. After addition of water (5 mL) it was extracted with ethyl acetate and the organic layer was washed with brine. It was dried over Na₂ SO₄ and evaporated in vacuo to give an oily residue. Column chromatography on silica gel (2:8 EtOAc-hexane) provided pure titled compound (38 mg).

Example 6 Preparation of (±)-4-Isopropylethynyl-4-trifluoromethyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

Part A: Preparation of 2-Iodo-4-methylaniline

To a stirred solution of p-toluidine (5 g, 46.7 mmol) in methylene chloride (25 mL) was added a solution of sodium bicarbonate (4.7 g, 56 mmol) in water (75 mL). Then was added iodine (11.26 g, 44.33 mmol) in small portions and the mixture was stirred for 16 hours at room temperature. The reaction was quenched with saturated NaHSO₃ and the product was extracted with methylene chloride. The methylene chloride layer was washed with brine, dried over Na₂ SO₄, and evaporated in vacuo to give a crude 2-iodo-4-methylaniline.

Part B: Preparation of Trimethylacetyl 2-iodo-4-methylanilide

To a stirred mixture of 2-iodo-4-methylaniline (46.7 mmol) in chloroform (50 mL) and 50 mL of saturated sodium carbonate was added trimethylacetyl chloride dropwise over a period of 15 minutes and the mixture was stirred vigorously for 45 minutes at room temperature. The product was extracted with chloroform, washed with water and dried over Na₂ SO₄. Evaporation of the solvent in vacuo affored the pivaloyl amide as a solid. It was recrystallized from ethyl acetate and hexane.

Part C: Preparation of Trimethylacetyl 4-methyl-2-trifluoroacetylanilide

To a stirred solution of trimethylacetyl 2-iodo-4-methylanilide (10.7 g, 33.75 mmol) in 50 mL of dry THF at -78° C. was added 1.6M-nBuLi in hexane (48.5 mL, 77.6 mmol) dropwise and the mixture was stirred for an hour at the same temperature. Then ethyl trifluoroacetate (9.6 mL, 81 mmol) was added dropwise and the mixture was stirred for 0.5 hours at -78° C. At the end of the stirring saturated NH₄ Cl solution was added and the mixture was warmed up to room temperature. The product was extracted with ethyl acetate, washed with water and brine, and dried over Na₂ SO₄. The solution was concentrated and the residue was column chromatographed on silica gel (1:9 EtOAc-hexane) to give the desired trimethylacetyl 4-methyl-2-trifluoroacetylanilide (1.29 g, 13% yield) and trimethylacetyl 4-methylanilide (major product).

Part D: Preparation of 4-Methyl-2-trifluoroacetylaniline

To a solution of trimethylacetyl 4-methyl-2-trifluoroacetylanilide (1.29 g) in 10 mL of dimethoxyethane was added 6N-HCl (5 mL) and the mixture was refluxed for 2.5 hours with stirring. After cooling it was poured over ice and was made basic with saturated NaHCO₃. The product was extracted with ethyl acetate, washed with brine, and dried over Na₂ SO₄. Evaporation of the solvent provided the aniline as a yellow solid in near quantitative yield.

Part E: Preparation of 2-Amino-5-methyl-α-isopropylethynyl-α-trifluoromethyl-benzyl alcohol

To stirred solution of 3-methyl-1-butyne (0.26 mL, 2.59 mmol) in 5 mL of dry THF at -20° C. was added 1.6M-nBuLi in hexane (1.4 mL, 2.24 mmol) dropwise and the mixture was warmed up to 0° C. over a period of 1 hour with stirring. It was the cooled back to -20° C. and was added dropwise a solution of 4-methyl-2-trifluoroacetylaniline (150 mg, 0.74 mmol) in 2 mL of THF. After stirring for an hour at -20°˜0° C. was added saturated NH₄ Cl (˜5 mL), and the product was extracted with ethyl acetate, washed with brine and dried over Na₂ SO₄. The solvents were evaporated off to give crude amino-alcohol as a yellow solid residue.

Part F: Preparation of 4-Isopropylethynyl-4-trifluoromethyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of the crude amino-alcohol (0.74 mmol) in dry toluene (7.5 mL) at -20° C. were added diisopropylethylamine (0.39 mL, 2.22 mmol) and 0.42 mL of 20% solution of phosgene in toluene dropwise and the mixture was stirred for 1 hour at -20°˜0° C. After addition of water (5 mL) it was extracted with ethyl acetate and the organic layer was washed with brine. It was dried over Na₂ SO₄ and evaporated in vacuo to give an oily residue. Column chromatography on silica gel (2:8 EtOAc-hexane) and recrystallization (EtOAc and hexane) provided pure titled compound (61 mg, 28% yield for 2 steps) as white crystals, mp 198°-199° C.

Example 7 Preparation of (±)-6-Acetyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 4-Amino-3-iodo-acetophenone

To a solution of 4-aminoacetophenone (5 g, 37 mmol) in 15 mL of CH₂ Cl₂ and 75 mL of water was added sodium bicarbonate (3.73 g, 44.4 mmol) followed by iodine (8.92 g, 35.1 mmol), and the mixture was stirred for 5 hours at room temperature. The reaction was quenched by portionwise addition of sodium bisulfite until the iodine color disappeared. The product was extracted with CH2Cl₂, washed with water, dried over Na₂ SO₄. Evaporation of the solvent gave crude 4-amino-3-iodo-acetophenone as solid (7.92 g).

Part B: Preparation of Trimethylacetyl 2-iodo-4-acetylanilide

To a stirred mixture of 4-amino-3-iodo-acetophenone (7.92 g, 30.3 mmol) in chloroform (50 mL) and 50 mL of saturated sodium carbonate was added trimethylacetyl chloride (7.8 mL, 63.7 mmol) dropwise over a period of 15 minutes and the mixture was stirred vigorously for 16 hours at room temperature. The product was extracted with chloroform, washed with water and dried over Na₂ SO₄. Evaporation of the solvent in vacuo affored the pivaloyl amide as a brown oil. It was column chromatographed (silica gel, 1:9 EtOAc-hexane) to afford pure trimethylacetyl 2-iodo-4-acetylanilide (5.83 g) as white crystals.

Part C: Preparation of Trimethylacetyl 2-iodo-4-(2-methyl-1,3-dithian-2-yl)anilide

To a stirred solution of trimethylacetyl 2-iodo-4-acetylanilide (2.9 g, 8.45 mmol) and 1,3-propanedithiol in 25 mL of THF at 0° C. was added borontrifluorate etherate (0.63 mL, 5.1 mmol) and the mixture was stirred for 16 hours at room temperature. Then was added second portion of borontrifluorate etherate (0.63 mL, 5.1 mmol) and it was continued to stir for 44 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water saturated NaHCO₃ and brine, dried over MgSO₄ and evaporated to a clear oil. It was column chromatographed (silica gel, 5:95 EtOAc-hexane) to give pure thioaketal as a foamy solid (2.85 g).

Part D: Preparation of Trimethylacetyl 4-(2-methyl-1,3-dithian-2-yl)-2-trifluoroacetylanilide

To a stirred solution of trimethylacetyl 2-iodo-4-(2-methyl-1,3-dithian-2-yl)anilide (2.29 g, 5.26 mmol) in 20 mL of dry THF at -78° C. was added 1.6M-nBuLi in hexane (6.7 mL, 10.7 mmol) dropwise and the mixture was stirred for 45 minutes at the same temperature. Then ethyl trifluoroacetate (12.6 mL, 105.2 mmol) was added dropwise and the mixture was gradually warmed up to room temperature over a period of 3 hours. At the end of the stirring saturated NH₄ Cl solution was added, and the product was extracted with ethyl acetate, washed with water and brine, and dried over Na₂ SO₄. The solution was concentrated and the residue was column chromatographed on silica gel (1:9 EtOAc-hexane) to give the desired trimethylacetyl 4-(2-methyl-1,3-dithian-2-yl)-2-trifluoroacetylanilide (0.63 g) and trimethylacetyl 4-(2-methyl-1,3-dithian-2-yl)anilide (1.33 g).

Part E: Preparation of 4-(2-Methyl-1,3-dithian-2-yl)-2-trifluoroacetylaniline

To a solution of trimethylacetyl 4-(2-methyl-1,3-dithian-2-yl)-2-trifluoroacetylanilide (0.63 g) in 10 mL of methanol was added 6N-HCl (2 mL) and the mixture was refluxed for 4 hours with stirring. After cooling it was poured over ice and was made basic with saturated NaHCO₃. The product was extracted with ethyl acetate, washed with brine, and dried over Na₂ SO₄. Evaporation of the solvent provided the desired 4-(2-methyl-1,3-dithian-2-yl)-2-trifluoroacetylaniline as a bright yellow solid.

Part F: Preparation of 2-Amino-5-(2-methyl-1,3-dithian-2-yl)-α-cyclopropylethynyl-α-trifluoromethyl-benzyl alcohol.

To stirred solution of cyclopropylacetylene (122 mg, 1.9 mmol) in 5 mL of dry THF at -20° C. was added 1.6M-nBuLi in hexane (0.99 mL, 1.59 mmol) dropwise and the mixture was warmed up to 0° C. over a period of 45 minutes with stirring. It was the cooled back to -20° C. and was added dropwise a solution of 4-methyl-2-trifluoroacetylaniline (150 mg, 0.74 mmol) in 2 mL of THF. After stirring for 1.5 hours at -20°˜0° C. was added saturated NH₄ Cl (˜5 mL), and the product was extracted with ethyl acetate, washed with brine and dried over Na₂ SO₄. The solvents were evaporated off to give crude amino-alcohol as a bright yellow solid residue.

Part G: Preparation of 4-Cyclopropylethynyl-4-trifluoromethyl-6-(2-methyl-1,3-dithian-2-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of the crude amino-alcohol (0.53 mmol) in dry toluene (5 mL) at -20° C. were added diisopropylethylamine (0.28 mL, 1.59 mmol) and 0.3 mL of 20% solution of phosgene in toluene dropwise and the mixture was stirred for 1.5 hours at -20˜0° C. and for 5 minutes at room temperature. After addition of water (5 mL) it was extracted with ethyl acetate and the organic layer was washed with brine. It was dried over Na₂ SO₄ and evaporated in vacuo to give an oily residue. It was purified by preparative TLC on a silica gel plate (3:7 EtOAc-hexane) to give pure titled compound (77 mg).

Part H: Preparation of 6-Acetyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a stirred solution of 4-cyclopropylethynyl-4-trifluoromethyl-6-(2-methyl-1,3-dithian-2-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (64 mg, 0.154 mmol) in 5 mL of methanol and 0.5 mL of water were added mercuric chloride (92 mg, 0.339 mmol) and mercuric oxide (50 mg, 0.23 mmol), and the mixture was refluxed for 2 hours. After cooling it was filtered through Celite and rinsed with EtOAc. The filtrate was washed with water and brine, dried over MgSO₄, and evaporated to give an oily residue. Column chromatography (silica gel, 2:8 EtOAc-hexane) afforded pure 6-6cetyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

Example 8 Preparation of (±)-5,6-Difluoro-4-(3-methyl)-1-buten-1-yl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 2,3-Difluoro-6-triphenylmethylamino-α-1-(3-methyl)-1-butynyl-α-trifluoromethyl-benzyl alcohol

To a solution of 3-methyl-1-butyne (0.73 g, 10.7 mmol) in dry THF (5 mL) at -20° C. was added 1.6M-nBuLi in hexane dropwise and the mixture was stirred for 15 minutes at the same temperature. Then a solution of 2,3-diflupro-6-triphenylmethylamino-α, α,α-trifluoroacetophenone (1 g, 2.14 mmol) in 5 mL of THF was added dropwise at -20° C. After stirring for 10 minutes, the cooling bath was removed and it was allowed to warm up to room temperature. The mixture was stirred for 45 minutes and was poured into saturated NH₄ Cl. The product was extracted with ether, washed with saturated NaHCO₃ and brine and dried over MgSO₄. Evaporation of solvent gave an oily residue, which was crystallized from methanol, ether and hexane mixture to provide pure product (0.432 g, 37.6%).

Part B: Preparation of 2,3-Difluoro-6-triphenylmethylamino-α-1-(3-methyl)-1-butenyl-α-trifluoromethyl-benzyl alcohol

To a solution of 2,3-difluoro-6-triphenylmethylamino-α-1-(3-methyl)-1-butynyl-α-trifluoromethyl-benzyl alcohol (0.431 g, 0.8 mmol) in 5 mL of dry THF was added 1M-lithium aluminumhydride in THF (2.41 mL, 2.41 mmol) at room temperature and the mixture was stirred for 1 hour. The reaction was quenched with several drops of saturated NH₄ Cl and was added about 20 mL of ether. After stirring for 10 minutes it was washed with saturated NaHCO₃ and dried over MgSO₄. Evaporation of the solvent gave the desired transolefinic compound in near quantitative yield.

Part C: Preparation of 6-Amino-2,3-Difluoro-α-1-(3-methyl)-1-butenyl-α-trifluoromethyl-benzyl alcohol

A solution of the crude product of step 2 (0.8 mmol) and 1.33 mL of c-HCl in methanol (5 mL) was stirred for 1 hour at room temperature and basified with saturated NaHCO3. It was extracted with ether and washed with brine. After drying over MgSO4, the solvent was evaporated off to give an oily residue. It was crystallized from hexane to give pure 6-amino-2,3-Difluoro-α-1-(3-methyl)-1-butenyl-α-trifluoromethyl-benzyl alcohol (0.184 g, 78%).

Part D: Preparation of 5,6-Difluoro-4-(3-methyl)-1-buten-1-yl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of the crude amino-alcohol (0.13 g, 0.44 mmol) in dry toluene (5 mL) at 0° C. were added diisopropylethylamine (0.23 mL, 1.32 mmol) and 0.24 mL of 2M-phosgene in toluene (0.48 mmol) dropwise and the mixture was stirred for 5 minutes at 0° C. and for 30 minutes at room temperature. After addition of saturated NH₄ Cl (5 mL) it was extracted with ether and the organic layer was washed with brine. It was dried over MgSO₄ and evaporated in vacuo to give an oily residue. It was purified by column chromatography on Silica gel (1:9 ether-hexane) to give pure titled compound (0.051 g, 36%).

Example 9 Preparation of (±)-4-Isopropylethynyl-4-trifluoromethyl-5,6-difluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one.

Part A: Preparation of N-trimethylacetyl-3,4-difluoroanilide

To a solution of 3,4-difluoroaniline (19 mL, 191 mmol) in methylene chloride (500 mL) at 0° was added triethylamine (32 mL, 230 mmol) followed dropwise with trimethylacetyl chloride (24 mL, 191 mmol) and the resulting reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was poured onto 3N HCl and extracted with methylene chloride (3×100 mL) and the combined organic extracts were dried over anhydrous NaSO₄ and concentrated in vacuo. The residue was taken up in hexanes (300 mL) and filtered through a sintered glass funnel. The solids are washed thoroughly with hexanes (500 mL) and dried under vacuum to give 37.36 g of the pivaloyl amide as a solid (40.68 g theoretical, 92% yield).

Part B: Preparation of N-Trimethylacetyl 5,6-difluoro-2-trifluoroacetylanilide

To a solution of N-trimethylacetyl-3,4-difluoroanilide (4.0 g, 14.6 mmol) in THF (60 mL) at -78° C. was added dropwise 1.6M nBuLi in hexane (22 mL, 35 mmol) and the resulting reaction mixture was allowed to stir at -78° C. for 1 h. The Ethyl trifluoroacetate (4 mL, 33.6 mmol) is added to the reaction mixture and the resulting solution was allowed to stir with warming to room temperature (ice bath removed after the addition of reagent) for 0.5 h. The reaction mixture was poured onto saturated NH₄ Cl and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo to give an orange oil. This product was used in the next step of the synthetic sequence without further purification.

Part C: Preparation of 5,6-Difluoro-2-trifluoroacetylaniline

To a solution of the orange oil in DME (15 mL) was added 6N HCl (75 mL) and the resulting mixture was allowed to reflux for 2 h. The reaction mixture was cooled, made basic with solid Na₂ CO₃ and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂, 20% EtOAc-hexanes eluant) provided 2110 mg of 5,6-Difluoro-2-trifluoroacetylaniline as a yellow solid (3285 mg theoretical, 64% yield).

Part D: Preparation of 2-Amino-5,6-difluoro-α-isopropylethynyl-α-trifluoromethyl-benzyl alcohol.

To a solution of 3-methyl-1-butyne (0.36 mL, 3.56 mmol) in THF (6 mL) at 0° C. was added 1.6M nBuLi in hexane (2.2 mL, 3.56 mmol) and the resulting reaction mixture was allowed to stir at 0° C. for 0.5 h. A solution of 5,6-Difluoro-2-trifluoroacetylaniline (200 mg, 0.89 mmol) in THF (6 mL) was added to the reaction mixture and the resulting reaction mixture was allowed to stir with warming to room temperature (ice bath removed after addition of reagent) for 0.5 h. The reaction mixture was poured onto saturated NH₄ Cl and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo to give an orange oil. This product was used in the next step of the synthetic sequence without further purification.

Part E: Preparation of 4-Isopropylethynyl-4-trifluoromethyl-5,6-difluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of amino-alcohol (crude product, 1.21 mmol) in toluene (4 mL) at 0° C. was added N,N-diisopropylethylamine (0.54 mL, 3.12 mmol) followed by a solution of 1.93M phosgene in toluene (0.6 mL, 1.16 mmol) and the resulting solution was allowed to stir at 0° C. for 0.1 h. The reaction mixture was poured onto water and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂, 20% EtOAc-hexanes eluant) provided 45 mg of the title compound (284 mg theoretical, 16% yield).

Example 10 Preparation of 2-Trifluoroacetylaniline

Part A: Preparation of 2-Amino-α-trifluoromethyl-benzyl alcohol

To a solution of amino ketone (155 mg, 0.7 mmol) in methanol (2 mL) at room temperature was added Pd(OH)₂ (20 mg) and hydrogenated (H₂ /balloon) for 2 h. The reaction mixture was filtered through Celite and concentrated in vacuo. The solids were triturated with ether (20 mL) and dried in vacuo to give 117 mg of 2-Amino-α-trifluoromethyl-benzyl alcohol as a pale yellow solid. (134 mg theoretical, 87% yield).

Part B: Preparation of 2-Trifluoroacetylaniline

To a slurry of amino alcohol (520 mg, 2.72 mmol) in methylene chloride (5 mL) at room temperature was added MnO₂ (10×wt, 5 g) and the resulting reaction mixture was allowed to stir at room temperature for 0.75 h. The reaction mixture was filtered through Celite and concentrated in vacuo to give an orange oil which is used without further purification due to instability of compound.

Example 11 Preparation of 3-Fluoro-2-trifluoroacetyl-triphenylmethylaniline

Part A: Preparation of 2-Amino-6-fluorobenzoyl N-methoxy-methylamide

To a solution of 2-amino-6-fluorobenzoic acid (5 g, 32.26 mmol) in AcCN (100 mL) at room temperature was added N,O-dimethylhydroxylamine hydrochloride (3.8 g, 38.71 mmol), EDAC (7.4 g, 38.71 mmol) followed by triethylamine (5.38 mL, 38.71 mmol) and the resulting reaction mixture was allowed to stir at room temperature for 6 h. The reaction mixture was poured onto saturated NaHCO₃ and extracted with EtOAc (3×100 mL). The combined EtOAc extracts were dried over anhydrous NaSO₄ and concentrated in vacuo. Chromatography (SiO₂, 25% EtOAc-hexanes eluant) provided 4.29 g of the desired compound (5.87 g theoretical, 73% yield).

Part B: Preparation of 2-Triphenylmethylamino-6-fluorobenzoyl N-methoxy-methylamide

To a solution of 2-amino-6-fluorobenzoyl N-methoxy-methylamide (300 mg, 2.14 mmol) in methylene chloride (10 mL) at room temperature was added N,N'-diisopropylamine (1.2 mL, 6.4 mmol) followed by triphenylmethyl bromide (830 mg, 2.57 mmol) and the resulting reaction mixture is allowed to stir at room temperature for 0.5 h. The reaction mixture was poured onto water and extracted with methylene chloride (3×50 mL) and the combined organic extracts were dried over anhydrous NaSO₄ and concentrated in vacuo. Chromatography (SiO₂, 10% EtOAc-hexanes) provided 832 mg of the desired compound (942 mg theoretical, 88% yield).

Part C: Preparation of 2-Triphenylmethylamino-6-fluorobenzaldehyde

To a solution of 2-triphenylmethylamino-6-fluorobenzoyl N-methoxy-methylamide (300 mg, 0.68 mmol) in THF (4 mL) at -78° C. was added lithium aluminum hydride (30 mg, 0.82 mmol) and the resulting reaction mixture was allowed to stir with warming to room temperature (dry ice bath removed after addition of reagent) for 1 h. The reaction mixture was quenched with 20% KHSO₄ and extracted with EtOAc (3×100 mL) and the combined EtOAc extracts were dried over anhydrous NaSO₄ and concentrated in vacuo. Chromatography (SiO₂, 5% EtOAc-hexanes) provided 182 mg of the title compound (260 mg theoretical, 70% yield).

Part D: Preparation of 2-Amino-6-fluoro-α-trifluoromethylbenzyl alcohol

To a solution of 2-triphenylmethylamino-6-fluorobenzaldehyde (100 mg, 0.24 mmol) in THF (2 mL) at 0° C. was added trifluoromethyltrimethylsilane (0.06 mL, 0.36 mmol) followed by a solution of tetrabutylammonium fluoride in THF (1M, 0.36 mL, 0.36 mmol) and the resulting reaction mixture was allowed to stir with warming to room temperature (ice bath removed after the addition of reagents) for 0.5 h. The reaction mixture was poured onto water and extracted with EtOAc (3×50 mL) and the combined EtOAc extracts were dried over anhydrous NaSO₄ and concentrated in vacuo. Chromatography (SiO₂, 10% EtOAc-hexanes) provided 88 mg of the title compound (108 mg theoretical, 82% yield).

Part E: Preparation of 3-Fluoro-2-trifluoroacetyl-triphenylmethylaniline

To a solution of 2-amino-6-fluoro-α-trifluoromethyl-benzyl alcohol (88 mg, 0.2 mmol) in methylene chloride (6 mL) at room temperature was added manganese(IV)oxide (900 mg, 10×wt) and the resulting reaction mixture was allowed to stir at room temperature for 5 h. The reaction mixture is filtered through Celite and concentrated in vacuo. Chromatography (SiO₂, 5% EtOAc-hexanes) provided 52 mg of the title compound (90 mg theoretical, 58% yield).

Example 12 Preparation of (±)-4-Cyclopropylethynyl-6-chloro-4-trifluoromethyl-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 5-(t-Butoxycarbonylamino)-2-chloropyridine

To a stirred solution of 2.83 g(22.0 mmol) of 5-amino-2-chloropyridine in 20 mL of anhydrous THF was added 44.0 mL(44.0 mmol) of a 1.0M solution of NaHMDS in toluene over 5 min. The dark solution was stirred 15 min. and 4.36 g(20 mmol) of di-t-butyldicarbonate in 5 mL of THF was introduced over 2 min. The thick mixture was stirred an additional 1 h and poured into 0.5N aq. HCl. The solution was extracted with ethyl acetate, and the organic extract was washed with saturated aq. NaHCO₃, water, and brine. The solution was dried (MgSO₄), concentrated under reduced pressure, and chromatographed on silica gel(gradient elution with 3:1 hexanes-ether then ether) to give, after evaporation of solvents, 3.81 g(83%) of 5-(t-butoxycarbonylamino)-2-chloropyridine as a white solid, mp 122°-123° C. ¹ H NMR (300 MHz, CDCl₃) δ8.23(d, 1H, J=2 Hz); 7.98(br. d, 1H, J=8 Hz); 7.25(d, 1H, J=8 Hz); 6.58(s, 1H); 1.52(s, 9H).

Part B: Preparation of 2-(5-(t-Butoxycarbonylamino)-2-chloropyrid-4-yl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol

To a stirred, cooled (-50° C.) solution of 643 mg(2.8 mmol) of 5-(t-butoxycarbonylamino)-2-chloropyridine in 8 mL of anhydrous THF was added 4.7 mL(7.0 mmol) of t-BuLi in pentane over 3 min. The solution was stirred an additional 35 min. at -50° C. after which time 1 mL(large excess) of 4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-one. The solution was stirred an additional 20 min., warming to ambient temperature. The reaction was poured into 10% aq. citric acid, and the mixture was extracted with 1:1 ether-ethyl acetate. The organic extract was washed with saturated aq. NaHCO₃, then brine, dried (MgSO₄), and concentrated under reduced pressure. Chromatography on silica gel(gradient elution with 6:1 then 3:1 hexanes-ethyl acetate) afforded, after removal of solvent, 620 mg(56%) of 2-(5-(t-butoxycarbonylamino)-2-chloropyrid-4-yl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol as an amorphous solid. Mass spec.(NH₃ --CI): 391((M+H)⁺, 100%); 291((M+H-t-Boc)⁺, 49%). ¹ H NMR(300 MHz , CDCl₃) δ9.08(br. s, 1H); 8.19(br. s, 1H); 7.59(s, 1H); 1.50(s, 9H); 1.37-1.43(m, 1H); 0.81-0.97(m, 4H).

Part C: Preparation of 4-Cyclopropylethynyl-6-chloro-4 trifluoromethyl-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a stirred solution of 230 mg(0.59 mmol) of 2-(5-(t-butoxycarbonylamino)-2-chloropyrid-4-yl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol in 6 mL of anhydrous toluene was added 0.92 mL of a 2.5M solution of n-BuLi in hexanes. The solution was brought to reflux and stirred 10 min. after which time an additional 0.10 mL of n-BuLi was added. The solution was stirred an additional 20 min. at reflux and cooled to ambient temperature. The reaction was poured into 10% aq. citric acid and extracted with ether. The organic extract was washed with brine, dried(MgSO₄), and concentrated under reduced pressure. Chromatography on silica gel (elution with 3:1 hexanes-ethyl acetate) afforded 25 mg (13%) of 4-cyclopropylethynyl-6-chloro-4-trifluoromethyl-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one as an amorphous solid. Mass spec.(NH₃ --CI): 334((M+NH₄)⁺, 100%); 317 ((M+H)⁺, 100%); 273((M+H--CO₂)⁺, 21%). ¹ H NMR(300 MHz , CDCl₃) δ9.62(br. s, 1H); 8.17(s, 1H); 7.44(s, 1H); 1.36-1.44(m, 1H); 0.82-0.99(m, 4H).

Example 13 Preparation of (±)-6-Chloro-4-(2-methoxyethoxy)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 4-Chloro-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a stirred, gently refluxing solution of 7.0 g(31.9 mmol) of 2-amino-5-methoxy-(1',1',1'-trifluoro)acetophenone in 27 mL of anhydrous toluene was added 24.8 mL(47.9 mmol) of a 1.93M solution of phosgene in toluene over 2 min.(Note: A dry ice-acetone cold finger is used to condense phosgene during this reaction.). The solution is warmed at reflux for 2 h, cooled, and charged with 15 mL of hexanes. Upon stirring overnight at ambient temperature a precipitate formed which was filtered, washed with hexanes, and briefly air-dried to give 5.06 g(60%) of 4-chloro-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as an off-white solid mp 112°-114° C. ¹ H NMR(300 MHz , CDCl₃) δ9.05(br. s, 1H); 7.07(br. s, 1H); 7.02(dd, 1H, J=8, 2 Hz); 6.90(d, 1H, J=8 Hz); 3.83(s, 3H).

Part B: Preparation of 6-Chloro-4-(2-methoxyethoxy)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of 0.15 mL of 2-methoxyethanol in 5 mL of anhydrous THF at ambient temperature was added 20 mg of 100% sodium hydride. After 20 min, 100 mg of 4,6-dichloro-4-(trifluoromethyl)benzoxazinone was added, and the resulting solution was stirred at ambient temperature for 30 min. The reaction mixture was poured onto aqueous ammonium chloride and was extracted with ethyl acetate. The organic extracts were washed with brine, dried and evaporated. The crude product was purified by preparative TLC on silica gel (elution with ethyl acetate/hexanes 1:1) to afford a material which was crystallized from ethyl acetate-hexanes to afford 81 mg (71%) of the title compound.

Example 14 Preparation of (±)-6-Chloro-4-propylamino-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of 230 mg of 4,6-dichloro-4-(trifluoromethyl)benzoxazinone in 20 mL of dry ether was added 0.250 mL of n-propylamine. After stirring 30 min at ambient temperature, the solution was partitioned between ether and water, and the organic layer was washed with brine, dried, and evaporated. The crude product was purified by column chromatography on silica gel (elution with ethyl acetate-hexanes 1:3) to afford after crystallization from hexanes 24 mg (9.7%) of the title compound.

Example 15 Preparation of (±)-6-Chloro-4- 2-(furan-2-yl)ethynyl!-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of 5.9 g (25 mmoles) of 1,1-dibromo-2-(furan-2-yl)ethylene in 124 mL of anhydrous THF at -20° was added dropwise 31.0 mL of 1.6M n-butyllithium in hexanes (50 mmoles). This solution was allowed to warm to ambient temperature over a period of 30 min, after which time it was cooled to -50°. 4,6-Dichloro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one (2.65 g, 9.27 mmoles) was added in one portion, and the resulting solution was allowed to warm to -35° over 40 min. The reaction was quenched by the addition of aqueous ammonium chloride, and this mixture was poured onto water and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and evaporated. The crude product was purified by column chromatography on silica gel (elution with 15% and 30% ethyl acetate in hexanes) affording 3.5 g of a solid which was recrystallized from ethyl acetate/hexanes to afford 3.03 g (95.7%) of the title compound.

Example 16 Preparation of (±)-4-(1-Butynyl)-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a stirred, cooled(-78° C.) solution of 0.5 g(excess) of 1-butyne in 3 mL of anhydrous THF was added 1.6 mL(4.0 mmol) of a 2.5M solution of n-BuLi in hexanes over 3 min. The solution was stirred 5 min. and charged with 266 mg(1.00 mmol) of 4-chloro-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a single portion. The solution was warmed to -10° C. over 20 min., whereupon it was quenched with 20% aqueous citric acid. The mixture was extracted with ether, and the organic extract was washed with saturated aq. NaHCO₃ then brine. The solution was concentrated under reduced pressure, and the crude product was recrystallized from ethyl acetate-hexanes to afford 144 mg(48%) of 4-(1-butynyl)-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid, mp 161°-162° C. ¹ H NMR(300 MHz, CDCl₃) δ8.81(br. s, 1H); 7.07(d, 1H, J=2 Hz); 6.94(dd, 1H, J=9, 2 Hz); 6.81(d, 1H, J=8 Hz); 3.82(s, 3H); 2.34(q, 2H, J=7 Hz); 1.22(t, 3H, J=7 Hz).

Example 17 Preparation of (±)-4-(1'-hydroxy)-cyclopropylethynyl-4-trifluoromethyl-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one ##STR35## Part A: Preparation of Methyl 1-hydroxy-1-cyclopropanecarboxylate

1-Hydroxy-1-cyclopropanecarboxylic acid (587 mg, 5.75 mmol) was dissolved in methanol (20 mL) under nitrogen. Thionyl chloride (4 drops) were added and the reaction was stirred overnight at room temperature. Triethylamine was then added until the reaction was alkaline as judged by moistened pH paper. The solvent was then removed on the rotary evaporator.

Part B: Preparation of Methyl 1-triisopropylsilylhydroxy-1-cyclopropanecarboxylate

The residue was then dissolved in dry methylene chloride (20 mL) under a nitrogen atmosphere. Dry 2,6-lutidine (distilled from calcium hydride, 1.0 mL, 8.62 mmol) was added and the reaction cooled to 0° C. Triisopropylsilyl trifluoromethanesulfonate (2.3 mL, 8.62 mmol) was then added dropwise and stirring continued for 1 hour. The reaction was then poured into 1N HCl and extracted with hexanes. The organic layer was washed successively with water and brine, then dried with magnesium sulfate, filtered and evaporated. The crude material was purified by flash chromatography (silica) using 19:1 hexanes/ethyl acetate. This provided the silyl methyl ester in 87% yield for two steps (1.35 g).

Part C: Preparation of 1-Triisopropylsilylhydroxy-1-cyclopropanemethanol

The silyl methyl ester (1.05 g, 3.86 mmol) was dissolved in hexane (12 mL) under nitrogen. The reaction was cooled in a dry ice/acetone bath and a solution of diisobutylaluminum hydride (1.5M in toluene, 6.4 mL, 9.64 mmol) was introduced dropwise. Stirring was continued for 2 hours when the reaction was quenched by the addition of methanol (12 mL). The reaction was warmed to room temperature and poured into a saturated aqueous solution of sodium potassium tartrate. The clarified solution was extracted with ether and the organic layer washed with water and brine. After drying over magnesium sulfate, the product was isolated by filtration and evaporation (894.4 mg, 95%). This material was of sufficient purity for direct use in the next step.

Part D: Preparation of 1-Triisopropylsilylhydroxy-1-cyclopropanecarboxaldehyde

A 100 mL flask was flame-dried and sealed under nitrogen. The flask was charged with dry methylene chloride (11 mL) and oxalyl chloride (0.44 mL, 5.07 mmol). The solution was cooled in a dry ice/acetone bath and dimethylsulfoxide was introduced (0.73 mL, 10.3 mmol). After stirring for 5 minutes, the starting material (1.065 g, 4.36 mmol) was added as a solution in methylene chloride (5.0 mL). After stirring for 20 minutes, triethylamine (3.1 mL, 22.4 mmol) was added and the reaction was allowed to warm to room temperature. The reaction was then poured into 1N HCl and extracted with ether. The organic layer was washed twice with water and once with brine. Drying with magnesium sulfate, filtration and evaporation then provided the crude product. This material was of sufficient purity for use in the next step.

Part E: Preparation of 1-Triisopropylsilylhydroxy-1-(2',2'-dibromoethene)cyclopropane

A 500 mL flask was charged with carbon tetrabromide (2.89 g, 8.72 mmol) dissolved in dry methylene chloride (87 mL,). The solution was cooled to -20° C. when triphenylphosphine (recrystallized from hexanes, 2.28 g, 8.72 mmol) was added and stirring continued for 45 minutes. The reaction was then cooled to -60° C. where the crude aldehyde (maximum of 4.36 mmol) dissolved in dry methylene chloride (40 mL) containing triethylamine (0.61 mL, 4.26 mmol) was added. Stirring was continued overnight with warming to room temperature. The reaction was then diluted with hexanes (1 1) and filtered through a pad of magnesium sulfate. Evaporation and purification by flash column chromatography (silica, hexanes) gave the desired dibromoolefin (35%, 607.1 mg).

Part F: Preparation of (±)-4-(1'-Triisopropylsilylhydroxy)-cyclopropylethynyl-4-trifluoromethyl-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one

A 50 mL two-necked flasked was flame-dried in vacuo and sealed under nitrogen. The dibromoolefin was dissolved in dry tetrahydrofuran (8.0 mL) and transferred to the reaction flask. The reaction was cooled to -78° C. and a solution of n-butyllithium (2.5M in hexanes, 1.2 mL, 2.96 mmol) was added dropwise. Stirring was continued for 20 minutes when a solution of the chlorobenzoxazinone (212 mg. 0.74 mmol) in dry tetrahydrofuran (2.0 mL) was added. The reaction was warmed to -60° C. and stirring continued for 30 minutes. The reaction was then poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine and then dried over magnesium sulfate. The crude product was isolated by filtration and evaporation. Flash chromatography (silica, 4:1 hexanes/ethyl acetate) gave the partially purified product (235 mg). A subsequent chromatography under similar conditions gave the desired material (35%, 118 mg) with suitable purity for the next step.

Part G: Preparation of 4-(1'-Hydroxy)-cyclopropylethynyl-4-trifluoromethyl-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one

The starting material (53.0 mg, 0.117 mmol) was dissolved in dry tetrahydrofuran (2.0 mL) under nitrogen. A solution of tetra-n-butylammonium fluoride (1M in tetrahydrofuran, 0.12 mL, 0.12 mmol) was added and stirring continued for 15 minutes. The reaction was then diluted with 1:1 hexanes/ethyl acetate and washed twice with water and once with brine. Drying with magnesium sulfate, filtration, and evaporation gave the crude product. The compound was purified by flash chromatography (silica, 4:1 hexanes,/ethyl acetate to 2:1 hexanes/ethyl acetate). The desired product was isolated in 74% yield (28.7 mg). m.p. 192°-194° C. HRMS: calculated for C₁₄ H₁₀ ClF₃ NO₃, M+H): 332.0301; found 332.0296.

Example 18 Preparation of (±)-4-isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 2-Triphenylmethylamino-5-fluoro-α-isopropylethynyl-α-trifluoromethyl-benzyl alcohol

To a solution of 3-methyl-1-butyne (0.16 mL, 1.51 mmol) in THF (2 mL) at 0° C. was added 1.6M nBuLi in hexane (0.84 mL, 1.34 mmol) and the resulting reaction mixture was allowed to stir at 0° C. for 0.5 h. A solution of 5-fluoro-2-trifluoroacetyl-triphenylmethylaniline (300 mg, 0.67 mmol) in THF (2 mL) was added to the reaction mixture and the resulting reaction mixture was allowed to stir at 0° C. for 0.5 h. The reaction mixture was poured onto saturated NH₄ Cl and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo to give an orange oil. This product was used in the next step of the synthetic sequence without further purification.

Part B: Preparation of 2-Amino-5-fluoro-α-isopropylethynyl-α-trifluoromethyl-benzyl alcohol

To a solution of the benzyl alcohol (crude product, approx. 0.67 mmol) in methanol (5 mL) at room temperature was added concentrated hydrochloric acid (0.1 mL) and the resulting reaction mixture was allowed to stir at room temperature for 0.25 h. The reaction mixture was quenched with saturated NaHCO₃ and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂, 15% EtOAc-hexanes eluant) provided 103 mg of the title compound (184 mg theoretical, 56% yield over two steps).

Part C: Preparation of 4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of amino-alcohol (103 mg 0.37 mmol) in toluene (3 mL) at 0° C. was added N,N-diisopropylethylamine (0.23 mL, 1.30 mmol) followed by a solution of 1.93M phosgene in toluene (0.25 mL, 0.48 mmol) and the resulting solution was allowed to stir at 0° C. for 0.1 h. The reaction mixture was poured onto water and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂, 20% EtOAc-hexanes eluant) provided 89 mg of the title compound (111 mg theoretical, 80% yield).

Example 19 Preparation of 4-Chloro-2-cyclopropylacetylaniline ##STR36##

Cyclopropyllithium was prepared by the procedure of Dakkouri (Chem. Ber. 1979, 112, 3523.). To a 3 neck 100 ml flask equipped with a magnetic stir bar, a thermocouple probe, a West condenser and a nitrogen line was charged 1.0 g (0.14 mol.) of freshly cleaned Li ribbon and 20 ml anhydrous ether. The mixture was cooled to 0° C. and 5.6 ml of cyclopropylbromide (70 mmol) in 10 ml of anhydrous ether was added dropwise. The bromide solution was added over 45 min. due to the exothermic nature of the metalation reaction. After the addition was complete the lithium reagent was aged for 30 min. then cooled to -65° C. A solution of 5.53 g (28 mmol.) of 5-chloroisatoic anhydride in 80 ml THF was prepared in a dry 3 neck flask and cooled to -40° C. The cyclopropyllithium solution was transferred via canula into the anhydride solution over 30 min. The resulting milky solution was aged for 1 h at -40° C. during which time the solution became clear with a pale green color. The anion solution was quenched by addition of 1M citric acid solution and then warmed to ambient temperature. The phases were separated and the organic layer washed with water and concentrated to provide a tacky yellow solid which was chromatographed on silica gel with ethyl acetate/hexanes (3:1) to provide 3.56 g of the title compound in 65% yield. Crystallization from heptane provides the title compound as a pale yellow solid: m.p. 73.7° C.; ¹ H NMR (300 MHz , CDCl₃) δ7.90 (d, J=1.5 Hz, 1H), 7.22 (dd, J=2.3, 8.7 Hz, 1H), 6.59 (d, J=8.7 Hz, 1H), 6.13 (brs, 2H), 2.56 (m, 1H),. 1.18 (m, 2H), 1.00 (m, 2H); ¹³ C NMR (75 MHz, CDCl₃) δ201.06, 148.23, 133.83, 130.41, 121.70, 119.69, 118.56, 17.37, 11.08; IR (cm⁻¹) 3315, 3012, 1628, 1582, 1533, 1481, 1464, 1414, 1389, 1343, 1313, 1217, 1183, 1158, 1082, 1053, 1032, 985, 893, 868, 813.

Example 20 Preparation of 4-Chloro-2-((cyclopropylenthynyl)acetyl)aniline ##STR37##

To a 3 neck 100 ml flask equipped with a magnetic stir bar, a thermocouple probe, a solid addition funnel and a nitrogen line was charged 3.7 g (56.0 mmol.) of cyclopropylacetylene and 30 ml of anhydrous THF. The solution was cooled to -60° C. and 30 ml (53.1 mmol.) of 1.8M hexyllithium in hexanes was added dropwise while maintaining the internal temperature below -20° C. The solution was aged at -40° C. for 30 min. and then 5 g (25.3 mmol.) of 5-chloroisatoic anhydride was added as a solid in small portions. The resulting solution was aged for 2 h at -40° C. during which time the solution became clear with a pale yellow color. The anion solution was quenched by addition of 1M citric acid solution and then warmed to ambient temperature. The phases were separated and the organic layer washed with water and concentrated to provide a an orange solid. The product was triturated with heptanes to provides 9 as a tan solid: ¹ H NMR (300 MHz, CDCl₃) δ8.43 (m, 1H), 8.02 (m, 1H), 7.36 (m, 1H), 1.48 (m, 1H),. 0.99 (m, 2H), 0.87 (m, 2H); IR (cm⁻¹) 2978, 2221, 1641, 1579, 1502, 1434, 1410, 1370, 1299, 1055, 906, 829, 731.

Example 21 Preparation of (S)-6-Chloro-4-(chloro)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one ##STR38##

To a 3 neck flask equipped with a magnetic stirrer, a thermocouple probe and a dry ice condenser was charged 25 g (0.11 mol.) of trifluoroketone 3 and 150 ml of anhydrous toluene. This yellow solution was then heated to gentle reflux and a solution (87 ml, 0.17 mol.) of phosgene (1.93M) in toluene was added subsurface. The solution was heated to reflux (temperature range at 104° to 110° C.) for 3 h after which time the yellow color had dissipated and the starting ketone was not detected by ¹ H NMR. The solution was cooled to ambient temperature and then concentrated to provide a heterogeneous solution. The product was triturated with heptane (100 ml) and filtered to provide 29.24 g (92%) of the desired chlorobenzoxazinone as a white solid. m.p. 140.8° C.; ¹ H NMR (300 MHz ) δ9.26 (b, 1H), 7.57 (s, 1H), 7.45 (dd, J=1.9, 8.3 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H); ¹³ C NMR (75 MHz) δ146.32, 132.88, 132.42, 130.27, 125.80, 122.83, 119.06, 116.79, 115.85, 0.013; ¹⁹ F NMR (282 MHz ) δ-79.5; IR (cm⁻¹) 3191, 1764, 1601, 1498, 1403, 1335, 1316, 1252, 1199, 1073, 991, 901, 874, 826, 683.

Example 22 Preparation of (±)-6-Chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one ##STR39##

To a 50 ml 3 neck flask equipped with a magnetic stir bar, a thermocouple probe and nitrogen inlet was charged 10 ml anhydrous THF and 2.2 eq cyclopropylacetylene (0.23 g, 3.4 mmol.). The solution was cooled to -50° C. and 2.0 eq. of n-hexyllithium in hexanes (1.8M, 1.8 ml, 3.26 mmol.) was added dropwise via syringe. The internal temperature was maintained below -30° C. during the organolithium charge. The solution was aged for 30 minutes and then a solution of 0.44 g (1.55 mmol.) of the chlorobenzoxazinone in 5 ml THF was added dropwise. The reaction solution was maintained below -20° C. during the addition. The mixture was aged at -20° C. for 4 h after which time all of the starting material had been consumed by TLC. The mixture was then quenched while cold with saturated ammonium chloride solution and the layers separated. The organic solution was dried over sodium sulfate, concentrated to provide a light yellow solid. The product was then triturated with heptanes to provide 0.47 g (95%) of racemic title product as a white solid. HPLC: 99.8 area %; m.p. 183°-6° C.; ¹ H NMR (400 MHz, DMSO-d₆) δ11.05 (s, 1H), 7.54 (dd, J=2.5, 7 Hz, 1H), 7.43 (d, J=2.5 Hz, 1H), 6.99 (d, J=7 Hz, 1H), 1.58 (m, 1H), 0.92 (m, 2H), 0.77 (m, 2H); ¹³ C NMR (100 MHz , DMSO-d₆) δ146.23, 134.71, 132.04, 126.93, 126.57, 122.24, 116.83, 114.08, 95.63, 77.62, 65.85, 8.48, 8.44, -1.32; ¹⁹ F NMR (282 MHz, DMSO-d₆) δ-81.1; IR (cm³¹ 1) 3316, 3094, 2250, 1752, 1602, 1498, 1196, 1186. HRMS calcd. for C₁₄ H₉ F₃ ClNO₂ (M+H) 316.0352, found 316.0338. Anal. Calcd. for C₁₄ H₉ F₃ ClNO₂ : C, 53.27; H, 2.87; N, 4.45; Cl 11.23; F, 18.05. Found: C, 53.15; H, 2.73; N, 4.37; Cl, 11.10; F, 17.84.

Example 23 Preparation of (S)-6-Chloro-4-(1-pyridylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one ##STR40##

To a 50 ml 3 neck flask equipped with a magnetic stir bar, thermocouple and nitrogen inlet was charged 20 ml anhydrous THF and 2.2 eq pyridylethyne (1.1 g, 10.2 mmol.). The solution was cooled to -50° C. and 2.0 eq. of n-hexyllithium in hexanes (1.8M, 4.0 ml, 10.0 mmol.) was added dropwise via syringe. The internal temperature was maintained below -30° C. during the organolithium charge. The solution was aged for 30 minutes and then a solution of 1.5 g (5.2 mmol.) of the chlorobenzoxazinone from Example 21 in 15 ml THF was added dropwise. The reaction solution was maintained above -20° C. during the addition. The mixture was aged at -20° C. for 2 h at which time all of the starting material had been consumed by TLC. The mixture was then quenched while cold with saturated ammonium chloride solution and the layers separated. The organic solution was dried over sodium sulfate, concentrated to provide a brown solid. The product was purified by flash chromatography (hexanes/ethyl acetate; 3:1) and then triturated with heptanes to provide 1.06 g (57%) of the title compound as a white solid. HPLC: 99.8 area %; m.p. 185.8° C.; ¹ H NMR (300 MHz) δ9.62 (s, 1H), 8.68 (d, J=4.2 Hz, 1H), 7.76 (dd, J=7.6, 9.5 Hz, 1H), 7.61 (d, J=5.7 Hz, 2H), 7.40 (m, 2H), 6.91 (d, J=8.7 Hz, 1H; ¹³ C NMR (75 MHz ) δ150.38, 148.20, 140.32, 136.57, 133.43, 132.06, 129.34, 128.30, 127.60, 124.65, 123.94, 120.13, 116.37, 114.01, 88.72, 78.75; ¹⁹ F NMR (282 MHz ) δ-81.4; IR (cm⁻¹)3245, 3157, 3069, 2946, 2876, 2252, 1757, 1603, 1581, 1498, 1467, 1428, 1401, 1305, 1256, 1243, 1186, 1142, 1401, 1304, 1256+, 1243, 1186, 1142, 1103, 1072, 1037, 997, 971, 940, 866, 822, 780, 740. MS FIA/PCI (M+H) 353 m/z.

Example 24 Preparation of (±)-6-Chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one ##STR41## Part A: Preparation of 1-(t-Butyldimethylsilyl)-2-cyclopropylacetylene

To a stirred, cooled (0° C.) solution of 188 mL (658 mmol) of a 3.5M solution of cyclopropylacetylene in toluene was added 200 mL of THF. The solution was re-cooled to 0° C. and treated with 264 mL (660 mmol) of a 2.5M solution of n-BuLi in hexanes over 15 min. The solution was stirred an additional 40 min. at 0° C. and treated with 100 g(663 mmol) of t-butyldimethylsilyl chloride in 60 mL of THF over 10 min. After stirring 90 min. at 0° C. the reaction was quenched with saturated aq. NH₄ Cl and poured into 500 mL of water. The mixture was extracted with 500 mL of ether, and the organic extract was washed three times with water and once with brine. Concentration under reduced pressure followed by distillation afforded 49 g(42%) of 1-(t-butyldimethylsilyl)-2-cyclopropylacetylene as a colorless oil (b.p. 39°-42° C. at 0.5 torr). ¹ H NMR(CDCl₃, 300 MHz ) δ1.17-1.24(m, 1H); 0.95(s, 9H); 0.61-0.75(m, 4H); 0.00(s, 6H).

Part B: Preparation of 1-Deutero-1-ethynylcyclpropane

To a stirred, cooled(-30° C.) solution of 130 g(720 mmol) of 1-(t-butyldimethylsilyl)-2-cyclopropylacetylene in 400 mL of THF was added 403 mL(1.01 mol) of a 2.5M solution of n-BuLi in hexanes over 15 min. The solution was stirred 1.5 h at -20° C. and then treated with 49 mL(1.2 mol) of CD₃ OD over 10 min. After stirring 10 min. at -10° C. the reaction was quenched with 10 mL of D₂ O, followed 15 min later with 1 L of 20% aq. citric acid. The mixture was extracted with 1 L of ether, and the organic extract was washed sequentially with water, sat'd aq. NaHCO₃, and brine. The solution was dried(MgSO₄), concentrated under reduced pressure, and re-dissolved in 300 mL of THF. This solution was treated with 780 mL(350 mmol) of a 1M solution of (n-Bu)₄ NF in THF and stirred 6 h at ambient temperature. The solution was cooled to 0° C., washed with 1 L of water, and the aqueous phase was extracted with 150 mL of p-xylene. The organic extract was washed with 500 mL of water, and the combined aqueous phases were extracted with 70 mL of p-xylene. The two organic phases were combined, and washed 5 times with water and once with brine, dried(MgSO₄), and distilled. The fraction which boiled up to 105° C. at ambient pressure was collected to give 88 g of a solution having a deuterocyclopropylacetylene concentration of c. 43%. The remainder is primarily THF with some xylene and some 1-butene.

Part C: Preparation of (±) 6-Chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a stirred, cooled(-60° C.) solution of 12.6 g of a 60% solution of 1-deutero-1-ethynylcyclpropane in 65 mL of anhydrous THF was added 41 or (102 mmol) of a 2.5M solution of n-BuLi in hexanes over 20 min. The solution was stirred 30 min. and charged with 9.7 g(33.9 mmol) of 4,6-dichloro-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one in 10 mL of THF over 2 min. The solution was warmed to -30° C. over 1 h, whereupon it was quenched with 20% aqueous citric acid. The mixture was extracted with ether, and the organic extract was washed with saturated aq. NaHCO₃ then brine. The solution was concentrated under reduced pressure, and the crude product was chromatographed on silica gel(elution with 2:1 hexanes-ether) to afford 5.8 g(54%) of (±) 6-chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid, mp 180°-°181° C. ¹ H NMR(300 MHz , CDCl₃) δ9.32(br. s, 1H); 7.50(m, 1H); 7.37(dd, 1H, J=8, 1 Hz); 6.95(d, 1H, J=8 Hz); 0.82-0.96(m, 4H). Chiral chromatographic resolution provides (-) 6-Chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid, mp 133°-134° C.

Example 25 Preparation of 4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 2-Amino-6-fluoro-α-trifluoromethyl-benzyl alcohol

To a solution of 2-triphenylmethylamino-6-fluorobenzaldehyde (100 mg, 0.24 mmol) in THF (2 mL) at 0° C. was added trifluoromethyltrimethylsilane (0.06 mL, 0.36 mmol) followed by a solution of tetrabutylammonium fluoride in THF (1M, 0.36 mL, 0.36 mmol) and the resulting reaction mixture was allowed to stir with warming to room temperature (ice bath removed after the addition of reagents) for 0.5 h. The reaction mixture was poured onto water and extracted with EtOAc (3×50 mL) and the combined EtOAc extracts were dried over anhydrous NaSO₄ and concentrated in vacuo. Chromatography (SiO₂, 10% EtOAc-hexanes) provided 88 mg of the title compound (108 mg theoretical, 82% yield).

Part B: Preparation of 3-Fluoro-2-trifluoroacetyl-triphenylmethylaniline

To a solution of 2-amino-6-fluoro-α-trifluoromethyl-benzyl alcohol (88 mg, 0.2 mmol) in methylene chloride (6 mL) at room temperature was added manganese(IV)oxide (900 mg, 10×wt) and the resulting reaction mixture was allowed to stir at room temperature for 5 h. The reaction mixture is filtered through Celite and concentrated in vacuo. Chromatography (SiO₂, 5% EtOAc-hexanes) provided 52 mg of the title compound (90 mg theoretical, 58% yield).

Part C: Preparation of 2-Triphenylmethylamino-6-fluoro-α-isopropylethynyl-α-trifluoromethyl-benzyl alcohol

To a solution of 3-methyl-1-butyne (0.15 mL, 1.51 mmol) in THF (2 mL) at 0° C. was added 1.6M nBuLi in hexane (0.84 mL, 1.34 mmol) and the resulting reaction mixture was allowed to stir at 0° C. for 0.5 h. A solution of 6-fluoro-2-trifluoroacetylaniline (300 mg, 0.67 mmol) in THF (2 mL) was added to the reaction mixture and the resulting reaction mixture was allowed to stir with warming to room temperature (ice bath removed after addition of reagent) for 0.5 h. The reaction mixture was poured onto saturated NH₄ Cl and extracted with ether (3×50mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo to give an orange oil. This product was used in the next step of the synthetic sequence without further purification.

Part D: Preparation of 4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of the crude trityl protected amino-alcohol (crude product, 0.67 mmol) in methanol (5 mL) at room temperature was added concentrated HCl (0.1 mL) and the resulting reaction mixture is allowed to stir at room temperature for 0.25 h. The reaction mixture is concentrated in vacuo and the residue is taken up in ether (10 mL) and washed with saturated NaHCO₃. The ether extracts were dried over anhydrous MgSO4 and concentrated in vacuo. Chromatography (SiO₂, 15% EtOAc-hexanes) provided 103 mg of the deprotected amino-alcohol (184 mg theoretical, 56%, yield).

To a solution of amino-alcohol (103 mg, 0.37 mmol) in toluene (3 mL) at 0° C. was added N,N-diisopropylethylamine (0.23 mL, 1.3 mmol) followed by a solution of 1.93M phosgene in toluene (0.25 mL, 0.48 mmol) and the resulting solution was allowed to stir at 0° C. for 1 h. The reaction mixture was poured onto water and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂, 20% EtOAc-hexanes eluant) provided 89 mg of the title compound (111 mg theoretical, 80% yield).

                                      TABLE 1     __________________________________________________________________________      ##STR42##                                      Mass     Ex. #        G      R.sup.1                  R.sup.2      m.p. (°C.)                                      Spec     __________________________________________________________________________      1 6-Cl, 8-OH               CF.sub.3                  C C-cycPr           332.0301     2(-)        6-Cl, 8-OH               CF.sub.3                  C C-cycPr    170-172     3(-)        6-Cl, 8-OH               CF.sub.3                  C C-cycpr      4 6-Cl, 8-F               CF.sub.3                  C C-cycPr    169-171                                      334.0244      5 6-CH.sub.3               iPr                  C C-cycpr      138-138.5                                      270.1494      6 6-CH.sub.3               CF.sub.3                  C C-ipr      198-199                                      298.1047      7 6-COCH.sub.3               CF.sub.3                  C C-cycpr    197-200      8 5,6-diF               CF.sub.3                  3-methyl-1-                  buten-1-yl      9 5,6-diF               CF.sub.3                  C C-ipr             319.0616     12 6-Cl, 7-aza               CF.sub.3                  C C-cycpr           317.0322     13 6-Cl   CF.sub.3                  methoxyethoxy     14 6-Cl   CF.sub.3                  n-propylamino     15 6-Cl   CF.sub.3                  furan-2-yl--     16 6-OMe  CF.sub.3                  C C-Et       161-162                                      300.0841     17 6-Cl   CF.sub.3     (1'-OH-cycpr)               332.0296     18 5-F    CF.sub.3     ipr     22 6-Cl   CF.sub.3     cycPr     316.0352     23 6-Cl   CF.sub.3     2-pyridyl 353                                      (M + H)     24 6-Cl   CF.sub.3     (1-deutero-        133-134                  cycloprop-1-yl)     25 5-F    CF.sub.3     iPr     26 6-Cl, 8-OMe               CF.sub.3                  C C-cycPr           346.0477     27 6-Cl, 7-OH               CF.sub.3                  C C-cycPr           332.0286     28 6-Cl, 8-F               CF.sub.3                  C C-Et       191-192                                      339.0525                                      (M + NH.sub.4.sup.+)     29 6-Cl, 8-F               CF.sub.3                  CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                               160-162                                      340                                      (MH.sup.+)     30 5,6-diF               CF.sub.3                  C C-cycPr           318.0550                                      (MH.sup.+)     31 5,6-diF               CF.sub.3                  C C-iPr      amorphous     32 5,6-diF               CF.sub.3                  C C-nPr             320.0691     33 5,6-diF               CF.sub.3                  C C-Et              306.0550                                      (MH.sup.+)     34 5,6-diF               CF.sub.3                  C C-Me       217     35 5,6-diF               CF.sub.3                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                      324.1008     36 5,6-diF               CF.sub.3                  CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                      324.1003     37 5,6-diF               CF.sub.3                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                      310.0878     38 5,6-OCH.sub.2 O               CF.sub.3                  C C-cycPr    223-225                                      326.0639     39 5,6-OCH.sub.2 O               CF.sub.3                  C C-iPr      240    328.0797     40 5,6-OCH.sub.2 O               CF.sub.3                  C C-nPr      208-210     41 5,6-OCH.sub.2 O               CF.sub.3                  C C-Et       230-232     42 5,6-OCH.sub.2 O               CF.sub.3                  CH.sub.2 C CCH.sub.2 CH.sub.3                               215-217                                      328.0800     43 5,6-OCH.sub.2 O               CF.sub.3                  CH.sub.2 C CCH.sub.3                               207-208                                      314.0640     44 5,6-OCH.sub.2 O               CF.sub.3                  CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                               199-200     45 6-OMe  CF.sub.3                  C C-cycPr    155-157                                      312.0835     46 6-OMe  CF.sub.3                  C C-cycPr    143-144                                      312.0843     47 6-ONe  CF.sub.3                  C C-cycPr    142-144                                      312.0836     48 6-OMe  CF.sub.3                  C C-iPr      158-159                                      314.0998     49 6-OMe  CF.sub.3                  C C-nPr      148-150                                      314.1007     50 6-OMe  CF.sub.3                  C C-Me       177-180                                      286.0691     51 6-OMe  CF.sub.3                  CH.sub.2 C CCH.sub.2 CH.sub.3                               119-122                                      314.0989     52 6-OMe  CF.sub.3                  CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                      318                                      (MH.sup.+)     53 6-OMe  CF.sub.3                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                      304.1167     54 6-OMe  CF.sub.3                  CH.sub.2 CH.sub.2 -Ph                                      352.1153     55 6-OMe, 8-F               CF.sub.3                  C C-cycPr    188-189                                      330.0738     56 6-NMe.sub.2               CF.sub.3                  C C-cycPr           325.1173     57 6-NMe.sub.2               CF.sub.3                  C C-iPr             327.1322     58 6-NMe.sub.2               CF.sub.3                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                      331.1641     59 6-NMe.sub.2               CF.sub.3                  CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                      331.1637     60 6-COCH.sub.3               CF.sub.3                  C C-Et       180-183     61 6-CH.sub.3               CF.sub.3                  C C-cycPr    189    296.0905     62 6-CH.sub.3               CF.sub.3                  C C-Et       222    284.0882     63 6,8-diCl               CF.sub.3                  C C-cycPr    152-153                                      348.9870     64 6,8-diCl               CF.sub.3                  CH.sub.2 CH.sub.2 -Ph                                      389.0188                                      (M.sup.+)     65 5,6,8-triF               CF.sub.3                  C C-cycPr    amorphous     66 5,6,8-triF               CF.sub.3                  C C-iPr      amorphous     67 5,6,8-triF               CF.sub.3                  C C-nPr      amorphous     68 5,6,8-triF               CF.sub.3                  C C-Et       amorphous     69 5,8-diF               CF.sub.3                  C C-cycPr           335.0834                                      (M + NH.sub.4.sup.+)     70 5,8-diF               CF.sub.3                  C C-iPr             320.0710                                      (MH.sup.+)     71 5,8-diF               CF.sub.3                  C C-nPr             337.0970                                      (M + NH.sub.4.sup.+)     72 5,8-diF               CF.sub.3                  C C-Et              323.8817                                      (M + NH.sub.4.sup.+)     73 6-iPr  CF.sub.3                  C C-cycPr           324.1203     74 6-iPr  CF.sub.3                  C C-iPr             326.1361     75 6-iPr  CF.sub.3                  C C-Ph              360.1204     76 6-iPr  CF.sub.3                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                      330.1672     77 6-iPr  CF.sub.3                  CH.sub.2 CH.sub.2 -iPr                                      330.1673     78 6-iPr  CF.sub.3                  CH.sub.2 CH.sub.2 -Ph                                      364.1517     79 6-OCF.sub.3               CF.sub.3                  C C-cycPr           366.0561     80 6-OCF.sub.3               CF.sub.3                  C C-iPr             368.0712     81 6-OCF.sub.3               CF.sub.3                  C C-Ph              401.0475     82 6-OCF.sub.3               CF.sub.3                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                      372.1018     83 6-OCF.sub.3               CF.sub.3                  CH.sub.2 CH.sub.2 -iPr                                      372.1039     84 6-OCF.sub.3               CF.sub.3                  CH.sub.2 CH.sub.2 -Ph                                      405.0795     85 H      CF.sub.3                  CH.sub.2 CH.sub.2 -Ph                                      282.0735     86 H      CF.sub.3                  C C-iPr             284.0894     87 H      CF.sub.3                  C C-Ph              318.0748     88 H      CF.sub.3                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                      288.1201     89 H      CF.sub.3                  CH.sub.2 CH.sub.2 -iPr                               121-122     90 H      CF.sub.3                  CH.sub.2 CH.sub.2 -Ph                                      322.1055     91 6-Ph   CF.sub.3                  C C-cycPr    185-186                                      358.1055     92 6-Ph   CF.sub.3                  C C-iPr      179-180                                      360.1211     93 6-Ph   CF.sub.3                  C C-nPr      143-144                                      360.1211     94 6-Ph   CF.sub.3                  C C-iBu      163-164                                      374.1352     95 6-Ph   CF.sub.3                  C C-Et       195    346.1055     96 6-Ph   CF.sub.3                  CH.sub.2 CH.sub.2 -iPr                               147-148                                      364.1524     97 6-OMe  iPr                  C C-cycPr           286.1428     98 6-OMe  iPr                  C C-iPr             288.1583     99 6-CH.sub.3               cycPr                  C C-iPr      133-134                                      270.1498     100        6-CH.sub.3               iPr                  C C-iPr      133-134                                      272.1648     101        6-CH.sub.3               Et C C-iPr      138-139                                      258.1505     102        6-CH.sub.3               Et C C-Et       138.5-139                                      244.1333     103        6,7-diCl               cycPr                  C C-iPr     104        6,7-diCl               iPr                  C C-iPr      amorphous     105        7-Cl   cycPr                  C C-cycPr           288.0783     106        7-Cl   cycPr                  C C-iPr             290.0941     107        7-Cl   cycPr                  C C-iBu      117-118                                      304.1110     108        7-Cl   iPr                  C C-cycPr           290.0940     109        7-Cl   iPr                  C C-iPr             292.1103     110        6-Cl, 8-aza               CF.sub.3                  C C-cycPr           317.0317     111        6-Cl, 8-aza               CF.sub.3                  C C-iPr             319                                      (MH.sup.+)     112        6-Cl, 8-aza               CF.sub.3                  CH.sub.2 CH.sub.2 -Ph                               214-215                                      357.0625     113        6-OCH.sub.3, 7-aza               CF.sub.3                  C C-cycPr    181-182                                      313.0800     114        6-aza  CF.sub.3                  C C-cycPr     __________________________________________________________________________      *Unless otherwise noted, stereochemistry is (+/-).

                  TABLE 2     ______________________________________      ##STR43##     Ex. #   G            R.sup.1 R.sup.2     ______________________________________     201     6-Cl, 8-F    CF.sub.3                                  C C-iPr     202     6-Cl, 8-F    CF.sub.3                                  C C-npr     203     6-Cl, 8-F    CF.sub.3                                  C C-Bu     204     6-Cl, 8-F    CF.sub.3                                  C C-iBu     205     6-Cl, 8-F    CF.sub.3                                  C C-tBu     206     6-Cl, 8-F    CF.sub.3                                  C C-Me     207     6-Cl, 8-F    CF.sub.3                                  C C-Ph     208     6-Cl, 8-F    CF.sub.3                                  C C-(2-Cl)Ph     209     6-Cl, 8-F    CF.sub.3                                  C C-(3-Cl)Ph     210     6-Cl, 8-F    CF.sub.3                                  C C-(2-F)Ph     211     6-Cl, 8-F    CF.sub.3                                  C C-(3-F)Ph     212     6-Cl, 8-F    CF.sub.3                                  C C-(2-OH)Ph     213     6-Cl, 8-F    CF.sub.3                                  C C-(3-OH)Ph     214     6-Cl, 8-F    CF.sub.3                                  C C-(2-OMe)Ph     215     6-Cl, 8-F    CF.sub.3                                  C C-(3-OMe)Ph     216     6-Cl, 8-F    CF.sub.3                                  C C-(2-CN)Ph     217     6-Cl, 8-F    CF.sub.3                                  C C-(3-CN)Ph     218     6-Cl, 8-F    CF.sub.3                                  C C-(2-NH.sub.2)Ph     219     6-Cl, 8-F    CF.sub.3                                  C C-(3-NH.sub.2)Ph     220     6-Cl, 8-F    CF.sub.3                                  C C-(2-NMe.sub.2)Ph     221     6-Cl, 8-F    CF.sub.3                                  C C-(3-NMe.sub.2)Ph     222     6-Cl, 8-F    CF.sub.3                                  C C-2-Pyridyl     223     6-Cl, 8-F    CF.sub.3                                  C C-3-Pyridyl     224     6-Cl, 8-F    CF.sub.3                                  C C-4-Pyridyl     225     6-Cl, 8-F    CF.sub.3                                  C C-2-furanyl     226     6-Cl, 8-F    CF.sub.3                                  C C-3-furanyl     227     6-Cl, 8-F    CF.sub.3                                  C C-2-thienyl     228     6-Cl, 8-F    CF.sub.3                                  C C-3-thienyl     229     6-Cl, 8-F    CF.sub.3                                  CHCH-cycPr     230     6-Cl, 8-F    CF.sub.3                                  CHCH-iPr     231     6-Cl, 8-F    CF.sub.3                                  CHCH-nPr     232     6-Cl, 8-F    CF.sub.3                                  CHCH-Bu     233     6-Cl, 8-F    CF.sub.3                                  CHCH-iBu     234     6-Cl, 8-F    CF.sub.3                                  CHCH-tBu     235     6-Cl, 8-F    CF.sub.3                                  CHCH-Et     236     6-Cl, 8-F    CF.sub.3                                  CHCH-Me     237     6-Cl, 8-F    CF.sub.3                                  CHCH-Ph     238     6-Cl, 8-F    CF.sub.3                                  CHCH-2-Pyridyl     239     6-Cl, 8-F    CF.sub.3                                  CHCH-3-Pyridyl     240     6-Cl, 8-F    CF.sub.3                                  CHCH-4-Pyridyl     241     6-Cl, 8-F    CF.sub.3                                  CHCH-2-furanyl     242     6-Cl, 8-F    CF.sub.3                                  CHCH-3-furanyl     243     6-Cl, 8-F    CF.sub.3                                  CHCH-2-thienyl     244     6-Cl, 8-F    CF.sub.3                                  CHCH-3-thienyl     245     6-Cl, 8-F    CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                  1     246     6-Cl, 8-F    CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     247     6-Cl, 8-F    CF.sub.3                                  CH.sub.2 CH.sub.2 -cycPr     248     6-Cl, 8-F    CF.sub.3                                  CH.sub.2 CH.sub.2 -tBu     249     6-Cl, 8-F    CF.sub.3                                  CH.sub.2 CH.sub.2 Ph     250     6-Cl, 8-F    CF.sub.3                                  CH.sub.2 CH.sub.2 -2-Pyridyl     251     6-Cl, 8-F    CF.sub.3                                  CH.sub.2 CH.sub.2 -3-Pyridyl     252     6-Cl, 8-F    CF.sub.3                                  CH.sub.2 CH.sub.2 -4-Pyridyl     253     6-Cl, 8-F    CF.sub.3                                  CH.sub.2 CH.sub.2 -2-furanyl     254     6-Cl, 8-F    CF.sub.3                                  CH.sub.2 CH.sub.2 -3-furanyl     255     6-Cl, 8-F    CF.sub.3                                  CH.sub.2 CH.sub.2 -2-thienyl     256     6-Cl, 8-F    CF.sub.3                                  CH.sub.2 CH.sub.2 -3-thienyl     257     5,6-diF      CF.sub.3                                  C CBu     258     5,6-diF      CF.sub.3                                  C C-iBu     259     5,6-diF      CF.sub.3                                  C C-tBu     260     5,6-diF      CF.sub.3                                  C CCH.sub.2 CH.sub.2 OH     261     5,6-diF      CF.sub.3                                  C C-CH(OH)Me     262     5,6-diF      CF.sub.3                                  C C-ph     263     5,6-diF      CF.sub.3                                  C C-(2-Cl)Ph     264     5,6-diF      CF.sub.3                                  C C-(3-Cl)Ph     265     5,6-diF      CF.sub.3                                  C C-(4-Cl)Ph     266     5,6-diF      CF.sub.3                                  C C-(2-F)Ph     267     5,6-diF      CF.sub.3                                  C C-(3-F)Ph     268     5,6-diF      CF.sub.3                                  C C(4-F)Ph     269     5,6-diF      CF.sub.3                                  C C-(2-OH)Ph     270     5,6-diF      CF.sub.3                                  C C-(3-OH)Ph     271     5,6-diF      CF.sub.3                                  C C-(4-OH)Ph     272     5,6-diF      CF.sub.3                                  C C-(2-OMe)Ph     273     5,6-diF      CF.sub.3                                  C C-(3-OMe)Ph     274     5,6-diF      CF.sub.3                                  C C-(4-OMe)Ph     275     5,6-diF      CF.sub.3                                  C C-(2-CN)Ph     276     5,6-diF      CF.sub.3                                  C C-(3-CN)Ph     277     5,6-diF      CF.sub.3                                  C C-(4-CN)Ph     278     5,6-diF      CF.sub.3                                  C C-(2-NO.sub.2)Ph     279     5,6-diF      CF.sub.3                                  C C-(3-NO.sub.2)Ph     280     5,6-diF      CF.sub.3                                  C C-(4-NO.sub.2)Ph     281     5,6-diF      CF.sub.3                                  C C-(2-NH.sub.2)Ph     282     5,6-diF      CF.sub.3                                  C C-(3-NH.sub.2)Ph     283     5,6-diF      CF.sub.3                                  C C-(4-NH.sub.2)Ph     284     5,6-diF      CF.sub.3                                  C C-(2-NMe.sub.2)Ph     285     5,6-diF      CF.sub.3                                  C C-(3-NMe.sub.2)Ph     286     5,6-diF      CF.sub.3                                  C C-(4-NMe.sub.2)Ph     287     5,6-diF      CF.sub.3                                  C C-2-Pyridyl     288     5,6-diF      CF.sub.3                                  C C-3-Pyridyl     289     5,6-diF      CF.sub.3                                  C C-4-Pyridyl     290     5,6-diF      CF.sub.3                                  C C-2-furanyl     291     5,6-diF      CF.sub.3                                  C C-3-furanyl     292     5,6-diF      CF.sub.3                                  C C-2-thienyl     293     5,6-diF      CF.sub.3                                  C C-3-thienyl     294     5,6-diF      CF.sub.3                                  C C-2-oxazolyl     295     5,6-diF      CF.sub.3                                  C C-2-thiazolyl     296     5,6-diF      CF.sub.3                                  C C-4-isoxazolyl     297     5,6-diF      CF.sub.3                                  C C-2-imidazolyl     298     5,6-diF      CF.sub.3                                  CH.sub.2 C CCH.sub.3     299     5,6-diF      CF.sub.3                                  CH.sub.2 C CCH.sub.2 CH.sub.3     300     5,6-diF      CF.sub.3                                  CHCH-cycPr     301     5,6-diF      CF.sub.3                                  CHCH-iPr     302     5,6-diF      CF.sub.3                                  CHCH-nPr     303     5,6-diF      CF.sub.3                                  CHCH-Bu     304     5,6-diF      CF.sub.3                                  CHCH-iBu     305     5,6-diF      CF.sub.3                                  CHCH-tBu     306     5,6-diF      CF.sub.3                                  CHCH-Et     307     5,6-diF      CF.sub.3                                  CHCH-Me     308     5,6-diF      CF.sub.3                                  CHCH-Ph     309     5,6-diF      CF.sub.3                                  CHCH-2-Pyridyl     310     5,6-diF      CF.sub.3                                  CHCH-3-Pyridyl     311     5,6-diF      CF.sub.3                                  CHCH-4-Pyridyl     312     5,6-diF      CF.sub.3                                  CHCH-2-furanyl     313     5,6-diF      CF.sub.3                                  CHCH-3-furanyl     314     5,6-diF      CF.sub.3                                  CHCH-2-thienyl     315     5,6-diF      CF.sub.3                                  CHCH-3-thienyl     316     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.3     317     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -cycPr     318     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -tBu     319     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 OH     320     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 CH(OH)Me     321     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 Ph     322     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(2-Cl)Ph     323     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(3-Cl)Ph     324     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(4-Cl)Ph     325     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(2-F)Ph     326     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(3-F)Ph     327     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(4-F)Ph     328     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(2-OH)Ph     329     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(3-OH)Ph     330     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(4-OH)Ph     331     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(2-OMe)Ph     332     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(3-OMe)Ph     333     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(4-OMe)Ph     334     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(2-CN)Ph     335     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(3-CN)Ph     336     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(4-CN)Ph     337     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(2-NO.sub.2)Ph     338     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(3-NO.sub.2)Ph     339     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(4-NO.sub.2)Ph     340     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(2-NH.sub.2)Ph     341     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(3-NH.sub.2)Ph     342     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(4-NH.sub.2)Ph     343     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(2-NMe.sub.2)Ph     344     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(3-NMe.sub.2)Ph     345     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -(4-NMe.sub.2)Ph     346     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -2-Pyridyl     347     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -3-Pyridyl     348     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -4-Pyridyl     349     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -2-furanyl     350     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -3-furanyl     351     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -2-thienyl     352     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -3-thienyl     353     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -2-oxazolyl     354     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -2-thiazolyl     355     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -4-isoxazolyl     356     5,6-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -2-imidazolyl     357     5,6-diCl     CF.sub.3                                  C C-cycPr     358     5,6-diCl     CF.sub.3                                  C C-iPr     359     5,6-diCl     CF.sub.3                                  C C-nPr     360     5,6-diCl     CF.sub.3                                  C C-Bu     361     5,6-diCl     CF.sub.3                                  C C-IBu     362     5,6-diCl     CF.sub.3                                  C C-tBu     363     5,6-diCl     CF.sub.3                                  C C-Et     364     5,6-diCl     CF.sub.3                                  C C-Me     365     5,6-diCl     CF.sub.3                                  C CCH.sub.2 CH.sub.2 OH     366     5,6-diCl     CF.sub.3                                  C C-CH(OH)Me     367     5,6-diCl     CF.sub.3                                  C CPh     368     5,6-diCl     CF.sub.3                                  C C-(2-Cl)Ph     369     5,6-diCl     CF.sub.3                                  C C-(3-Cl)Ph     370     5,6-diCl     CF.sub.3                                  C C-(4-Cl)Ph     371     5,6-diCl     CF.sub.3                                  C C-(2-F)Ph     372     5,6-diCl     CF.sub.3                                  C C-(3-F)Ph     373     5,6-diCl     CF.sub.3                                  C C-(4-F)Ph     374     5,6-diCl     CF.sub.3                                  C C-(2-OH)Ph     375     5,6-diCl     CF.sub.3                                  C C-(3-OH)Ph     376     5,6-diCl     CF.sub.3                                  C C-(4-OH)Ph     377     5,6-diCl     CF.sub.3                                  C C-(2-OMe)Ph     378     5,6-diCl     CF.sub.3                                  C C-(3-OMe)Ph     379     5,6-diCl     CF.sub.3                                  C C-(4-OMe)Ph     380     5,6-diCl     CF.sub.3                                  C C-(2-CN)Ph     381     5,6-diCl     CF.sub.3                                  C C-(3-CN)Ph     382     5,6-diCl     CF.sub.3                                  C C-(4-CN)Ph     383     5,6-diCl     CF.sub.3                                  C C-(2-NO.sub.2)Ph     384     5,6-dlCl     CF.sub.3                                  C C-(3-NO.sub.2)Ph     385     5,6-diCl     CF.sub.3                                  C C-(4-NO.sub.2)Ph     386     5,6-diCl     CF.sub.3                                  C C-(2-NH.sub.2)Ph     387     5,6-diCl     CF.sub.3                                  C C-(3-NH.sub.2)Ph     388     5,6-diCl     CF.sub.3                                  C C-(4-NH.sub.2)Ph     389     5,6-diCl     CF.sub.3                                  C C-(2-NMe.sub.2)Ph     390     5,6-diCl     CF.sub.3                                  C C-(3-NMe.sub.2)Ph     391     5,6-diCl     CF.sub.3                                  C C-(4-NMe.sub.2)Ph     392     5,6-diCl     CF.sub.3                                  C C-2-Pyridyl     393     5,6-diCl     CF.sub.3                                  C C-3-Pyridyl     394     5,6-diCl     CF.sub.3                                  C C-4-Pyridyl     395     5,6-diCl     CF.sub.3                                  C C-2-furanyl     396     5,6-diCl     CF.sub.3                                  C C-3-furanyl     397     5,6-diCl     CF.sub.3                                  C C-2-thienyl     398     5,6-diCl     CF.sub.3                                  C C-3-thienyl     399     5,6-diCl     CF.sub.3                                  CHCH-cycPr     400     5,6-diCl     CF.sub.3                                  CHCH-iPr     401     5,6-diCl     CF.sub.3                                  CHCH-nPr     402     5,6-diCl     CF.sub.3                                  CHCH-Bu     403     5,6-diCl     CF.sub.3                                  CHCH-iBu     404     5,6-diCl     CF.sub.3                                  CHCH-tBu     405     5,6-diCl     CF.sub.3                                  CHCH-Et     406     5,6-diCl     CF.sub.3                                  CHCH-Me     407     5,6-diCl     CF.sub.3                                  CHCH-Ph     408     5,6-diCl     CF.sub.3                                  CHCH-2-Pyridyl     409     5,6-diCl     CF.sub.3                                  CHCH-3-Pyridyl     410     5,6-diCl     CF.sub.3                                  CHCH-4-Pyridyl     411     5,6-diCl     CF.sub.3                                  CHCH-2-furanyl     412     5,6-diCl     CF.sub.3                                  CHCH-3-furanyl     413     5,6-diCl     CF.sub.3                                  CHCH-2-thienyl     414     5,6-diCl     CF.sub.3                                  CHCH-3-thienyl     415     5,6-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                  4     416     5,6-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2     417     5,6-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     418     5,6-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 -cycPr     419     5,6-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 -tBu     420     5,6-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 OH     421     5,6-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 CH(OH)Me     422     5,6-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 Ph     423     5,6-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 -2-Pyridyl     424     5,6-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 -3-Pyridyl     425     5,6-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 -4-Pyridyl     426     5,6-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 -2-furanyl     427     5,6-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 -3-furanyl     428     5,6-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 -2-thienyl     429     5,6-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 -3-thienyl     430     5-Cl,6-F     CF.sub.3                                  C C-cycPr     431     5-Cl,6-F     CF.sub.3                                  C C-iPr     432     5-Cl,6-F     CF.sub.3                                  C C-nPr     433     5-Cl,6-F     CF.sub.3                                  C CBu     434     5-Cl,6-F     CF.sub.3                                  C C-iBu     435     5-Cl,6-F     CF.sub.3                                  C C-tBu     436     5-Cl,6-F     CF.sub.3                                  C C-Et     437     5-Cl,6-F     CF.sub.3                                  C CMe     438     5-Cl,6-F     CF.sub.3                                  C CCH.sub.2 CH.sub.2 OH     439     5-Cl,6-F     CF.sub.3                                  C CCH(CH)Me     440     5-Cl,6-F     CF.sub.3                                  C CPh     441     5-Cl,6-F     CF.sub.3                                  C C-(2-Cl)Ph     442     5-Cl,6-F     CF.sub.3                                  C C-(3-Cl)Ph     443     5-Cl,6-F     CF.sub.3                                  C C-(4-Cl)Ph     444     5-Cl,6-F     CF.sub.3                                  C C-(2-F)Ph     445     5-Cl,6-F     CF.sub.3                                  C C-(3-F)Ph     446     5-Cl,6-F     CF.sub.3                                  C C-(4-F)Ph     447     5-Cl,6-F     CF.sub.3                                  C C-(2-OH)Ph     448     5-Cl,6-F     CF.sub.3                                  C C-(3-OH)Ph     449     5-Cl,6-F     CF.sub.3                                  C C-(4-OH)Ph     450     5-Cl,6-F     CF.sub.3                                  C C-(2-OMe)Ph     451     5-Cl,6-F     CF.sub.3                                  C C-(3-OMe)Ph     452     5-Cl,6-F     CF.sub.3                                  C C-(4-OMe)Ph     453     5-Cl,6-F     CF.sub.3                                  C C-(2-CN)Ph     454     5-Cl,6-F     CF.sub.3                                  C C-(3-CN)Ph     455     5-Cl,6-F     CF.sub.3                                  C C-(4-CN)Ph     456     5-Cl,6-F     CF.sub.3                                  C C-(2-NO.sub.2)Ph     457     5-Cl,6-F     CF.sub.3                                  C C-(3-NO.sub.2)Ph     458     S-Cl,6-F     CF.sub.3                                  C C-(4-NO.sub.2)Ph     459     5-Cl,6-F     CF.sub.3                                  C C-(2-NH.sub.2)Ph     460     5-Cl,6-F     CF.sub.3                                  C C-(3-NH.sub.2)Ph     461     5-Cl,6-F     CF.sub.3                                  C C-(4-NH.sub.2)Ph     462     5-Cl,6-F     CF.sub.3                                  C C-(2-NMe.sub.2)Ph     463     5-Cl,6-F     CF.sub.3                                  C C-(3-NMe.sub.2)Ph     464     5-Cl,6-F     CF.sub.3                                  C C-(4-NMe.sub.2)Ph     465     5-Cl,6-F     CF.sub.3                                  C C-2-Pyridyl     466     5-Cl,6-F     CF.sub.3                                  C C-3-Pyridyl     467     5-Cl,6-F     CF.sub.3                                  C C-4-Pyridyl     468     5-Cl,6-F     CF.sub.3                                  C C-2-furanyl     469     5-Cl,6-F     CF.sub.3                                  C C-3-furanyl     470     5-Cl,6-F     CF.sub.3                                  C C-2-thienyl     471     5-Cl,6-F     CF.sub.3                                  C C-3-thienyl     472     5-Cl,6-F     CF.sub.3                                  CHCH-cycPr     473     5-Cl,6-F     CF.sub.3                                  CHCH-iPr     474     5-Cl,6-F     CF.sub.3                                  CHCH-nPr     475     5-Cl,6-F     CF.sub.3                                  CHCH-Bu     476     5-Cl,6-F     CF.sub.3                                  CHCH-iBu     477     5-Cl,6-F     CF.sub.3                                  CHCH-tBu     478     5-Cl,6-F     CF.sub.3                                  CHCHEt     479     5-Cl,6-F     CF.sub.3                                  CHCHMe     480     5-Cl,6-F     CF.sub.3                                  CHCHPh     481     5-Cl,6-F     CF.sub.3                                  CHCH-2-Pyridyl     482     5-Cl,6-F     CF.sub.3                                  CHCH-3-Pyridyl     483     5-Cl,6-F     CF.sub.3                                  CHCH-4-Pyridyl     484     5-Cl,6-F     CF.sub.3                                  CHCH-2-furanyl     485     5-Cl,6-F     CF.sub.3                                  CHCH-3-furanyl     486     5-Cl,6-F     CF.sub.3                                  CHCH-2-thienyl     487     5-Cl,6-F     CF.sub.3                                  CHCH-3-thienyl     488     5-Cl,6-F     CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                  .     489     5-Cl,6-F     CF.sub.3                                  CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2     490     5-Cl,6-F     CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     491     5-Cl,6-F     CF.sub.3                                  CH.sub.2 CH.sub.2 -cycPr     492     5-Cl,6-F     CF.sub.3                                  CH.sub.2 CH.sub.2 -tBu     493     5-Cl,6-F     CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 OH     494     5-Cl,6-F     CF.sub.3                                  CH.sub.2 CH.sub.2 CH(OH)Me     495     5-Cl,6-F     CF.sub.3                                  CH.sub.2 CH.sub.2 Ph     496     5-Cl,6-F     CF.sub.3                                  CH.sub.2 CH.sub.2 -2-Pyridyl     497     5-Cl,6-F     CF.sub.3                                  CH.sub.2 CH.sub.2 -3-Pyridyl     498     5-Cl,6-F     CF.sub.3                                  CH.sub.2 CH.sub.2 -4-Pyridyl     499     5-Cl,6-F     CF.sub.3                                  CH.sub.2 CH.sub.2 -2-furanyl     500     5-Cl,6-F     CF.sub.3                                  CH.sub.2 CH.sub.2 -3-furanyl     501     5-Cl,6-F     CF.sub.3                                  CH.sub.2 CH.sub.2 -2-thienyl     502     5-Cl,6-F     CF.sub.3                                  CH.sub.2 CH.sub.2 -3-thienyl     503     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-Bu     504     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-iBu     505     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-tBu     506     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-Me     507     5,6-OCH.sub.2 O                          CF.sub.3                                  C CCH.sub.2 CH.sub.2 OH     508     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-CH(OH)Me     509     5,6-OCH.sub.2 O                          CF.sub.3                                  C CPh     510     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-(2-Cl)Ph     511     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-(3-Cl)Ph     512     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-(4-Cl)Ph     513     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-(2-F)Ph     514     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-(3-F)Ph     515     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-(4-F)Ph     516     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-(2-OH)Ph     517     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-(3-OH)Ph     518     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-(4-OH)Ph     519     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-(2-OMe)Ph     520     S,6-OCH.sub.2 O                          CF.sub.3                                  C C-(3-OMe)Ph     521     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-(4-OMe)Ph     522     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-(2-CN)Ph     523     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-(3-CN)Ph     524     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-(4-CN)Ph     525     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-(2-NO.sub.2)Ph     526     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-(3-NO.sub.2)Ph     527     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-(4-NO.sub.2)Ph     528     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-(2-NH.sub.2)Ph     529     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-(3-NH.sub.2)Ph     530     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-(4-NH.sub.2)Ph     531     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-(2-NMe.sub.2)Ph     532     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-(3-NMe.sub.2)Ph     533     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-(4-NMe.sub.2)Ph     534     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-2-Pyridyl     535     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-3-Pyridyl     536     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-4-Pyridyl     537     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-2-furanyl     538     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-3-furanyl     539     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-2-thienyl     540     5,6-OCH.sub.2 O                          CF.sub.3                                  C C-3-thienyl     541     5,6-OCH.sub.2 O                          CF.sub.3                                  CHCH-cycPr     542     5,6-OCH.sub.2 O                          CF.sub.3                                  CHCH-iPr     543     5,6-OCH.sub.2 O                          CF.sub.3                                  CHCH-nPr     544     5,6-OCH.sub.2 O                          CF.sub.3                                  CHCH-Bu     545     5,6-OCH.sub.2 O                          CF.sub.3                                  CHCH-iBu     546     5,6-OCH.sub.2 O                          CF.sub.3                                  CHCH-tBu     547     5,6-OCH.sub.2 O                          CF.sub.3                                  CHCH-Et     548     5,6-OCH.sub.2 O                          CF.sub.3                                  CHCH-Me     549     5,6-OCH.sub.2 O                          CF.sub.3                                  CHCH-Ph     550     5,6-OCH.sub.2 O                          CF.sub.3                                  CHCH-2-Pyridyl     551     5,6-OCH.sub.2 O                          CF.sub.3                                  CHCH-3-Pyridyl     552     5,6-OCH.sub.2 O                          CF.sub.3                                  CHCH-4-Pyridyl     553     5,6-OCH.sub.2 O                          CF.sub.3                                  CHCH-2-furanyl     554     5,6-OCH.sub.2 O                          CF.sub.3                                  CHCH-3-furanyl     555     5,6-OCH.sub.2 O                          CF.sub.3                                  CHCH-2-thienyl     556     5,6-OCH.sub.2 O                          CF.sub.3                                  CHCH-3-thienyl     557     5,6-OCH.sub.2 O                          CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                  7     558     5,6-OCH.sub.2 O                          CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     559     5,6-OCH.sub.2 O                          CF.sub.3                                  CH.sub.2 CH.sub.2 -cycPr     560     5,6-OCH.sub.2 O                          CF.sub.3                                  CH.sub.2 CH.sub.2 -tBu     561     5,6-OCH.sub.2 O                          CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 OH     562     5,6-OCH.sub.2 O                          CF.sub.3                                  CH.sub.2 CH.sub.2CH(OH)Me     563     5,6-OCH.sub.2 O                          CF.sub.3                                  CH.sub.2 CH.sub.2 Ph     564     5,6-OCH.sub.2 O                          CF.sub.3                                  CH.sub.2 CH.sub.2 -2-Pyridyl     565     5,6-OCH.sub.2 O                          CF.sub.3                                  CH.sub.2 CH.sub.2 -3-Pyridyl     566     5,6-OCH.sub.2 O                          CF.sub.3                                  CH.sub.2 CH.sub.2 -4-Pyridyl     567     5,6-OCH.sub.2 O                          CF.sub.3                                  CH.sub.2 CH.sub.2 -2-furanyl     568     5,6-OCH.sub.2 O                          CF.sub.3                                  CH.sub.2 CH.sub.2 -3-furanyl     569     5,6-OCH.sub.2 O                          CF.sub.3                                  CH.sub.2 CH.sub.2 -2-thienyl     570     5,6-OCH.sub.2 O                          CF.sub.3                                  CH.sub.2 CH.sub.2 -3-thienyl     571     5-F          CF.sub.3                                  C C-cycPr     572     5-F          CF.sub.3                                  C C-iPr     573     5-F          CF.sub.3                                  C C-nPr     574     5-F          CF.sub.3                                  C C-Bu     575     5-F          CF.sub.3                                  C C-iBu     576     5-F          CF.sub.3                                  C C-tBu     577     5-F          CF.sub.3                                  C C-Et     578     5-F          CF.sub.3                                  C C-Me     579     5-F          CF.sub.3                                  C CCH.sub.2 CH.sub.2 OH     580     5-F          CF.sub.3                                  C C-CH(OH)Me     581     5-F          CF.sub.3                                  C C-Ph     582     5-F          CF.sub.3                                  C C-(2-Cl)Ph     583     5-F          CF.sub.3                                  C C-(3-Cl)Ph     584     5-F          CF.sub.3                                  C C-(4-Cl)Ph     585     5-F          CF.sub.3                                  C C-(2-F)Ph     586     5-F          CF.sub.3                                  C C-(3-F)Ph     587     5-F          CF.sub.3                                  C C-(4-F)Ph     588     5-F          CF.sub.3                                  C C-(2-OH)Ph     589     5-F          CF.sub.3                                  C C-(3-OH)Ph     590     5-F          CF.sub.3                                  C C-(4-OH)Ph     591     5-F          CF.sub.3                                  C C-(2-OMe)Ph     592     5-F          CF.sub.3                                  C C-(3-OMe)Ph     593     5-F          CF.sub.3                                  C C-(4-OMe)Ph     594     5-F          CF.sub.3                                  C C-(2-CN)Ph     595     5-F          CF.sub.3                                  C C-(3-CN)Ph     596     5-F          CF.sub.3                                  C C-(4-CN)Ph     597     5-F          CF.sub.3                                  C C-(2-NO.sub.2)Ph     598     5-F          CF.sub.3                                  C C-(3-NO.sub.2)Ph     599     5-F          CF.sub.3                                  C C-(4-NO.sub.2)Ph     600     5-F          CF.sub.3                                  C C-(2-NH.sub.2)Ph     601     5-F          CF.sub.3                                  C C-(3-NH.sub.2)Ph     602     5-F          CF.sub.3                                  C C-(4-NH.sub.2)Ph     603     5-F          CF.sub.3                                  C C-(2-NMe.sub.2)Ph     604     5-F          CF.sub.3                                  C C-(3-NMe.sub.2)Ph     605     5-F          CF.sub.3                                  C C-(4-NMe.sub.2)Ph     606     5-F          CF.sub.3                                  C C-2-Pyridyl     607     5-F          CF.sub.3                                  C C-3-Pyridyl     608     5-F          CF.sub.3                                  C C-4-Pyridyl     609     5-F          CF.sub.3                                  C C-2-furanyl     610     5-F          CF.sub.3                                  C C-3-furanyl     611     5-F          CF.sub.3                                  C C-2-thienyl     612     5-F          CF.sub.3                                  C C-3-thienyl     613     5-F          CF.sub.3                                  CHCH-cycPr     614     5-F          CF.sub.3                                  CHCH-iPr     615     5-F          CF.sub.3                                  CHCH-nPr     616     5-F          CF.sub.3                                  CHCH-Bu     617     5-F          CF.sub.3                                  CHCH-iBu     618     5-F          CF.sub.3                                  CHCH-tBu     619     5-F          CF.sub.3                                  CHCH-Et     620     5-F          CF.sub.3                                  CHCH-Me     621     5-F          CF.sub.3                                  CHCH-Ph     622     5-F          CF.sub.3                                  CHCH-2-Pyridyl     623     5-F          CF.sub.3                                  CHCH-3-Pyridyl     624     5-F          CF.sub.3                                  CHCH-4-Pyridyl     625     5-F          CF.sub.3                                  CHCH-2-furanyl     626     5-F          CF.sub.3                                  CHCH-3-furanyl     627     5-F          CF.sub.3                                  CHCH-2-thienyl     628     5-F          CF.sub.3                                  CHCH-3-thienyl     629     5-F          CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                  2     630     5-F          CF.sub.3                                  CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2     631     5-F          CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     632     5-F          CF.sub.3                                  CH.sub.2 CH.sub.2 -cycPr     633     5-F          CF.sub.3                                  CH.sub.2 CH.sub.2 -tBu     634     5-F          CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 OH     635     5-F          CF.sub.3                                  CH.sub.2 CH.sub.2 CH(OH)Me     636     5-F          CF.sub.3                                  CH.sub.2 CH.sub.2 Ph     637     5-F          CF.sub.3                                  CH.sub.2 CH.sub.2 -2-Pyridyl     638     5-F          CF.sub.3                                  CH.sub.2 CH.sub.2 -3-Pyridyl     639     5-F          CF.sub.3                                  CH.sub.2 CH.sub.2 -4-Pyridyl     640     5-F          CF.sub.3                                  CH.sub.2 CH.sub.2 -2-furanyl     641     5-F          CF.sub.3                                  CH.sub.2 CH.sub.2 -3-furanyl     642     5-F          CF.sub.3                                  CH.sub.2 CH.sub.2 -2-thienyl     643     5-F          CF.sub.3                                  CH.sub.2 CH.sub.2 -3-thienyl     644     5-Cl         CF.sub.3                                  C C-cycPr     645     5-Cl         CF.sub.3                                  C C-iPr     646     5-Cl         CF.sub.3                                  C C-nPr     647     5-Cl         CF.sub.3                                  C C-Bu     648     5-Cl         CF.sub.3                                  C C-iBu     649     5-Cl         CF.sub.3                                  C C-tBu     650     5-Cl         CF.sub.3                                  C C-Et     651     5-Cl         CF.sub.3                                  C CMe     652     5-Cl         CF.sub.3                                  C CCH.sub.2 CH.sub.2 OH     653     5-Cl         CF.sub.3                                  C CCH(OH)Me     654     5-Cl         CF.sub.3                                  C CPh     655     5-Cl         CF.sub.3                                  C C-(2-Cl)Ph     656     5-Cl         CF.sub.3                                  C C-(3-Cl)Ph     657     5-Cl         CF.sub.3                                  C C-(4-Cl)Ph     658     5-Cl         CF.sub.3                                  C C-(2-F)Ph     659     5-Cl         CF.sub.3                                  C C-(3-F)Ph     660     5-Cl         CF.sub.3                                  C C-(4-F)Ph     661     5-Cl         CF.sub.3                                  C C-(2-OH)Ph     662     5-Cl         CF.sub.3                                  C C-(3-OH)Ph     663     5-Cl         CF.sub.3                                  C C-(4-OH)Ph     664     5-Cl         CF.sub.3                                  C C-(2-OMe)Ph     665     5-Cl         CF.sub.3                                  C C-(3-OMe)Ph     666     5-Cl         CF.sub.3                                  C C-(4-OMe)Ph     667     5-Cl         CF.sub.3                                  C C-(2-CN)Ph     668     5-Cl         CF.sub.3                                  C C-(3-CN)Ph     669     5-Cl         CF.sub.3                                  C C-(4-CN)Ph     670     5-Cl         CF.sub.3                                  C C-(2-NO.sub.2)Ph     671     5-Cl         CF.sub.3                                  C C-(3-NO.sub.2)Ph     672     5-Cl         CF.sub.3                                  C C-(4-NO.sub.2)Ph     673     5-Cl         CF.sub.3                                  C C-(2-NH.sub.2)Ph     674     5-Cl         CF.sub.3                                  C C-(3-NH.sub.2)Ph     675     5-Cl         CF.sub.3                                  C C-(4-NH.sub.2)Ph     676     5-Cl         CF.sub.3                                  C C-(2-NMe.sub.2)Ph     677     5-Cl         CF.sub.3                                  C C-(3-NMe.sub.2)Ph     678     5-Cl         CF.sub.3                                  C C-(4-NMe.sub.2)Ph     679     5-Cl         CF.sub.3                                  C C-2-Pyridyl     680     5-Cl         CF.sub.3                                  C C-3-Pyridyl     681     5-Cl         CF.sub.3                                  C C-4-Pyridyl     682     5-Cl         CF.sub.3                                  C C-2-furanyl     683     5-Cl         CF.sub.3                                  C C-3-furanyl     684     5-Cl         CF.sub.3                                  C C-2-thienyl     685     5-Cl         CF.sub.3                                  C C-3-thienyl     686     5-Cl         CF.sub.3                                  CHCH-cycPr     687     5-Cl         CF.sub.3                                  CHCH-iPr     688     5-Cl         CF.sub.3                                  CHCH-nPr     689     5-Cl         CF.sub.3                                  CHCH-Bu     690     5-Cl         CF.sub.3                                  CHCH-iBu     691     5-Cl         CF.sub.3                                  CHCH-tBu     692     5-Cl         CF.sub.3                                  CHCHEt     693     5-Cl         CF.sub.3                                  CHCHMe     694     5-Cl         CF.sub.3                                  CHCHPh     695     5-Cl         CF.sub.3                                  CHCH-2-Pyridyl     696     5-Cl         CF.sub.3                                  CHCH-3-Pyridyl     697     5-Cl         CF.sub.3                                  CHCH-4-Pyridyl     698     5-Cl         CF.sub.3                                  CHCH-2-furanyl     699     5-Cl         CF.sub.3                                  CHCH-3-furanyl     700     5-Cl         CF.sub.3                                  CHCH-2-thienyl     701     5-Cl         CF.sub.3                                  CHCH-3-thienyl     702     5-Cl         CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                  N     703     5-Cl         CF.sub.3                                  CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2     704     5-Cl         CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     705     5-Cl         CF.sub.3                                  CH.sub.2 CH.sub.2 -cycPr     706     5-Cl         CF.sub.3                                  CH.sub.2 CH.sub.2 -tBu     707     5-Cl         CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 OH     708     5-Cl         CF.sub.3                                  CH.sub.2 CH.sub.2 CH(OH)Me     709     5-Cl         CF.sub.3                                  CH.sub.2 CH.sub.2 Ph     710     5-Cl         CF.sub.3                                  CH.sub.2 CH.sub.2 -2-Pyridyl     711     5-Cl         CF.sub.3                                  CH.sub.2 CH.sub.2 -3-Pyridyl     712     5-Cl         CF.sub.3                                  CH.sub.2 CH.sub.2 -4-Pyridyl     713     5-Cl         CF.sub.3                                  CH.sub.2 CH.sub.2 -2-furanyl     714     5-Cl         CF.sub.3                                  CH.sub.2 CH.sub.2 -3-furanyl     715     5-Cl         CF.sub.3                                  CH.sub.2 CH.sub.2 -2-thienyl     716     5-c1         CF.sub.3                                  CH.sub.2 CH.sub.2 -3-thienyl     717     6-OMe        CF.sub.3                                  C C-Bu     718     6-OMe        CF.sub.3                                  C C-iBu     719     6-OMe        CF.sub.3                                  C C-tBu     720     6-OMe        CF.sub.3                                  C CCH.sub.2 CH.sub.2 OH     721     6-OMe        CF.sub.3                                  C C-CH(OH)Me     722     6-OMe        CF.sub.3                                  C CPh     723     6-OMe        CF.sub.3                                  C C-(2-Cl)Ph     724     6-OMe        CF.sub.3                                  C C-(3-Cl)Ph     725     6-OMe        CF.sub.3                                  C C-(4-Cl)Ph     726     6-OMe        CF.sub.3                                  C C-(2-F)Ph     727     6-OMe        CF.sub.3                                  C C-(3-F)Ph     728     6-OMe        CF.sub.3                                  C C-(4-F)Ph     729     6-OMe        CF.sub.3                                  C C-(2-OH)Ph     730     6-OMe        CF.sub.3                                  C C-(3-OH)Ph     731     6-OMe        CF.sub.3                                  C C-(4-OH)Ph     732     6-OMe        CF.sub.3                                  C C-(2-OMe)Ph     733     6-OMe        CF.sub.3                                  C C-(3-OMe)Ph     734     6-OMe        CF.sub.3                                  C C-(4-OMe)Ph     735     6-OMe        CF.sub.3                                  C C-(2-CN)Ph     736     6-OMe        CF.sub.3                                  C C-(3-CN)Ph     737     6-OMe        CF.sub.3                                  C C-(4-CN)Ph     738     6-OMe        CF.sub.3                                  C C-(2-NO.sub.2)Ph     739     6-OMe        CF.sub.3                                  C C-(3-NO.sub.2)Ph     740     6-OMe        CF.sub.3                                  C C-(4-NO.sub.2)Ph     741     6-OMe        CF.sub.3                                  C C-(2-NH.sub.2)Ph     742     6-OMe        CF.sub.3                                  C C-(3-NH.sub.2)Ph     743     6-OMe        CF.sub.3                                  C C-(4-NH.sub.2)Ph     744     6-OMe        CF.sub.3                                  C C-(2-NMe.sub.2)Ph     745     6-OMe        CF.sub.3                                  C C-(3-NMe.sub.2)Ph     746     6-OMe        CF.sub.3                                  C C-(4-NMe.sub.2)Ph     747     6-OMe        CF.sub.3                                  C C-2-Pyridyl     748     6-OMe        CF.sub.3                                  C C-3-Pyridyl     749     6-OMe        CF.sub.3                                  C C-4-Pyridyl     750     6-OMe        CF.sub.3                                  C C-2-furanyl     751     6-OMe        CF.sub.3                                  C C-3-furanyl     752     6-OMe        CF.sub.3                                  C C-2-thienyl     753     6-OMe        CF.sub.3                                  C C-3-thienyl     754     6-OMe        CF.sub.3                                  C C-2-oxazolyl     755     6-OMe        CF.sub.3                                  C C-2-thiazolyl     756     6-OMe        CF.sub.3                                  C C-4-isoxazolyl     757     6-OMe        CF.sub.3                                  C C-2-imidazolyl     758     6-OMe        CF.sub.3                                  CH.sub.2 C CCH.sub.3     759     6-OMe        CF.sub.3                                  CHCH-cycPr     760     6-OMe        CF.sub.3                                  CHCH-iPr     761     6-OMe        CF.sub.3                                  CHCH-nPr     762     6-OMe        CF.sub.3                                  CHCH-Bu     763     6-OMe        CF.sub.3                                  CHCH-iBu     764     6-OMe        CF.sub.3                                  CHCH-tBu     765     6-OMe        CF.sub.3                                  CHCHEt     766     6-OMe        CF.sub.3                                  CHCHMe     767     6-OMe        CF.sub.3                                  CHCHPh     768     6-OMe        CF.sub.3                                  CHCH-2-Pyridyl     769     6-OMe        CF.sub.3                                  CHCH-3-Pyridyl     770     6-OMe        CF.sub.3                                  CHCH-4-pyridyl     771     6-OMe        CF.sub.3                                  CHCH-2-furanyl     772     6-OMe        CF.sub.3                                  CHCH-3-furanyl     773     6-OMe        CF.sub.3                                  CHCH-2-thienyl     774     6-OMe        CF.sub.3                                  CHCH-3-thienyl     775     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                  N     776     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.3     777     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -cycPr     778     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -tBu     779     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 OH     780     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -CH(OH)Me     781     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(2-Cl)Ph     782     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(3-Cl)Ph     783     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(4-Cl)Ph     784     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(2-F)Ph     785     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(3-F)Ph     786     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(4-F)Ph     787     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(2-OH)Ph     788     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(3-OH)Ph     789     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(4-OH)Ph     790     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(2-OMe)Ph     791     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(3-OMe)Ph     792     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(4-OMe)Ph     793     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(2-CN)Ph     794     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(3-CN)Ph     795     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(4-CN)Ph     796     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(2-NO.sub.2)Ph     797     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(3-NO.sub.2)Ph     798     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(4-NO.sub.2)Ph     799     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(2-NH.sub.2)Ph     800     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(3-NH.sub.2)Ph     801     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(4-NH.sub.2)Ph     802     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(2-NMe.sub.2)Ph     803     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(3-NMe.sub.2)Ph     804     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -(4-NMe.sub.2)Ph     805     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -2-Pyridyl     806     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -3-Pyridyl     807     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -4-Pyridyl     808     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -2-furanyl     809     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -3-furanyl     810     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -2-thienyl     811     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -3-thienyl     812     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -2-oxazolyl     813     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -2-thiazolyl     814     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -4-isoxazolyl     815     6-OMe        CF.sub.3                                  CH.sub.2 CH.sub.2 -2-imidazolyl     816     6-OMe, 8-F   CF.sub.3                                  C C-iPr     817     6-OMe, 8-F   CF.sub.3                                  C C-nPr     818     6-OMe, 8-F   CF.sub.3                                  C C-Et     819     6-OMe, 8-F   CF.sub.3                                  C CMe     820     6-OMe, 8-F   CF.sub.3                                  C CPh     821     6-OMe, 8-F   CF.sub.3                                  C C-2-Pyridyl     822     6-OMe, 8-F   CF.sub.3                                  C C-3-Pyridyl     823     6-OMe, 8-F   CF.sub.3                                  C C-4-Pyridyl     824     6-OMe, 8-F   CF.sub.3                                  C C-2-furanyl     825     6-OMe, 8-F   CF.sub.3                                  C C-3-furanyl     826     6-OMe, 8-F   CF.sub.3                                  C C-2-thienyl     827     6-OMe, 8-F   CF.sub.3                                  C C-3-thienyl     828     6-ONe, 8-F   CF.sub.3                                  CHCH-cycPr     829     6-OMe, 8-F   CF.sub.3                                  CHCH-iPr     830     6-OMe, 8-F   CF.sub.3                                  CHCH-nPr     831     6-OMe, 8-F   CF.sub.3                                  CHCHEt     832     6-OMe, 8-F   CF.sub.3                                  CHCHMe     833     6-OMe, 8-F   CF.sub.3                                  CHCHPh     834     6-OMe, 8-F   CF.sub.3                                  CHCH-2-Pyridyl     835     6-OMe, 8-F   CF.sub.3                                  CHCH-3-Pyridyl     836     6-OMe, 8-F   CF.sub.3                                  CHCH-4-Pyridyl     837     6-OMe, 8-F   CF.sub.3                                  CHCH-2-furanyl     838     6-OMe, 8-F   CF.sub.3                                  CHCH-3-furanyl     839     6-OMe, 8-F   CF.sub.3                                  CHCH-2-thienyl     840     6-OMe, 8-F   CF.sub.3                                  CHCH-3-thienyl     841     6-OMe, 8-F   CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                  N     842     6-OMe, 8-F   CF.sub.3                                  CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2     843     6-OMe, 8-F   CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     844     6-OMe, 8-F   CF.sub.3                                  CH.sub.2 CH.sub.2 -cycPr     845     6-OMe, 8-F   CF.sub.3                                  CH.sub.2 CH.sub.2 Ph     846     6-OMe, 8-F   CF.sub.3                                  CH.sub.2 CH.sub.2 -2-Pyridyl     847     6-OMe, 8-F   CF.sub.3                                  CH.sub.2 CH.sub.2 -3-Pyridyl     848     6-OMe, 8-F   CF.sub.3                                  CH.sub.2 CH.sub.2 -4-Pyridyl     849     6-OMe, 8-F   CF.sub.3                                  CH.sub.2 CH.sub.2 -2-furanyl     850     6-OMe, 8-F   CF.sub.3                                  CH.sub.2 CH.sub.2 -3-furanyl     851     6-OMe, 8-F   CF.sub.3                                  CH.sub.2 CH.sub.2 -2-thienyl     852     6-OMe, 8-F   CF.sub.3                                  CH.sub.2 CH.sub.2 -3-thienyl     853     5-F, 6-OMe   CF.sub.3                                  C C-cycPr     854     5-F, 6-OMe   CF.sub.3                                  C C-iPr     855     5-F, 6-OMe   CF.sub.3                                  C C-nPr     856     5-F, 6-OMe   CF.sub.3                                  C C-Bu     857     5-F, 6-OMe   CF.sub.3                                  C C-iBu     858     5-F, 6-OMe   CF.sub.3                                  C C-tBu     859     5-F, 6-OMe   CF.sub.3                                  C CEt     860     5-F, 6-OMe   CF.sub.3                                  C CMe     861     5-F, 6-OMe   CF.sub.3                                  C CPh     862     5-F, 6-OMe   CF.sub.3                                  C C-(2-Cl)Ph     863     5-F, 6-OMe   CF.sub.3                                  C C-(3-Cl)Ph     864     5-F, 6-OMe   CF.sub.3                                  C C-(2-F)Ph     865     5-F, 6-OMe   CF.sub.3                                  C C-(3-F)Ph     866     5-F, 6-OMe   CF.sub.3                                  C C-(2-OH)Ph     867     5-F, 6-OMe   CF.sub.3                                  C C-(3-OH)Ph     868     5-F, 6-OMe   CF.sub.3                                  C C-(2-OMe)Ph     869     5-F, 6-OMe   CF.sub.3                                  C C-(3-OMe)Ph     870     5-F, 6-OMe   CF.sub.3                                  C C-(2-CN)Ph     871     5-F, 6-OMe   CF.sub.3                                  C C-(3-CN)Ph     872     5-F, 6-OMe   CF.sub.3                                  C C-(2-NH.sub.2)Ph     873     5-F, 6-OMe   CF.sub.3                                  C C-(3-NH.sub.2)Ph     874     5-F, 6-OMe   CF.sub.3                                  C C-(2-NMe.sub.2)Ph     875     5-F, 6-OMe   CF.sub.3                                  C C-(3-NMe.sub.2)Ph     876     5-F, 6-OMe   CF.sub.3                                  C C-2-Pyridyl     877     5-F, 6-OMe   CF.sub.3                                  C C-3-Pyridyl     878     5-F, 6-OMe   CF.sub.3                                  C C-4-Pyridyl     879     5-F, 6-OMe   CF.sub.3                                  C C-2-furanyl     880     5-F, 6-OMe   CF.sub.3                                  C C-3-furanyl     881     5-F, 6-OMe   CF.sub.3                                  C C-2-thienyl     882     5-F, 6-OMe   CF.sub.3                                  C C-3-thienyl     883     5-F, 6-OMe   CF.sub.3                                  CHCH-cycPr     884     5-F, 6-OMe   CF.sub.3                                  CHCH-iPr     885     5-F, 6-OMe   CF.sub.3                                  CHCH-nPr     886     5-F, 6-OMe   CF.sub.3                                  CHCH-Bu     887     5-F, 6-OMe   CF.sub.3                                  CHCH-iBu     888     5-F, 6-OMe   CF.sub.3                                  CHCH-tBu     889     5-F, 6-OMe   CF.sub.3                                  CHCHEt     890     5-F, 6-OMe   CF.sub.3                                  CHCHMe     891     5-F, 6-OMe   CF.sub.3                                  CHCHPh     892     5-F, 6-OMe   CF.sub.3                                  CHCH-2-Pyridyl     893     5-F, 6-OMe   CF.sub.3                                  CHCH-3-Pyridyl     894     5-F, 6-OMe   CF.sub.3                                  CHCH-4-Pyridyl     895     5-F, 6-OMe   CF.sub.3                                  CHCH-2-furanyl     896     5-F, 6-OMe   CF.sub.3                                  CHCH-3-furanyl     897     5-F, 6-OMe   CF.sub.3                                  CHCH-2-thienyl     898     5-F, 6-OMe   CF.sub.3                                  CHCH-3-thienyl     899     5-F, 6-OMe   CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                  N     900     5-F, 6-OMe   CF.sub.3                                  CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2     901     5-F, 6-OMe   CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     902     5-F, 6-OMe   CF.sub.3                                  CH.sub.2 CH.sub.2 -cycPr     903     5-F, 6-OMe   CF.sub.3                                  CH.sub.2 CH.sub.2 -tBu     904     5-F, 6-OMe   CF.sub.3                                  CH.sub.2 CH.sub.2 Ph     905     5-F, 6-OMe   CF.sub.3                                  CH.sub.2 CH.sub.2 -2-Pyridyl     906     5-F, 6-OMe   CF.sub.3                                  CH.sub.2 CH.sub.2 -3-Pyridyl     907     5-F, 6-OMe   CF.sub.3                                  CH.sub.2 CH.sub.2 -4-Pyridyl     908     5-F, 6-OMe   CF.sub.3                                  CH.sub.2 CH.sub.2 -2-furanyl     909     5-F, 6-OMe   CF.sub.3                                  CH.sub.2 CH.sub.2 -3-furanyl     910     5-F, 6-OMe   CF.sub.3                                  CH.sub.2 CH.sub.2 -2-thienyl     911     5-F, 6-OMe   CF.sub.3                                  CH.sub.2 CH.sub.2 -3-thienyl     912     6-NMe.sub.2  CF.sub.3                                  C C-nPr     913     6-NMe.sub.2  CF.sub.3                                  C C-Bu     914     6-NMe.sub.2  CF.sub.3                                  C C-iBu     915     6-NMe.sub.2  CF.sub.3                                  C C-tBu     916     6-NMe.sub.2  CF.sub.3                                  C CEt     917     6-NMe.sub.2  CF.sub.3                                  C CMe     918     6-NMe.sub.2  CF.sub.3                                  C CPh     919     6-NMe.sub.2  CF.sub.3                                  C C-(2-Cl)Ph     920     6-NMe.sub.2  CF.sub.3                                  C C-(3-Cl)Ph     921     6-NMe.sub.2  CF.sub.3                                  C C-(2-F)Ph     922     6-NMe.sub.2  CF.sub.3                                  C C-(3-F)Ph     923     6-NMe.sub.2  CF.sub.3                                  C C-(2-OH)Ph     924     6-NMe.sub.2  CF.sub.3                                  C C-(3-OH)Ph     925     6-NMe.sub.2  CF.sub.3                                  C C-(2-OMe)Ph     926     6-NMe.sub.2  CF.sub.3                                  C C-(3-OMe)Ph     927     6-NMe.sub.2  CF.sub.3                                  C C-(2-CN)Ph     928     6-NMe.sub.2  CF.sub.3                                  C C-(3-CN)Ph     929     6-NMe.sub.2  CF.sub.3                                  C C-(2-NH.sub.2)Ph     930     6-NMe.sub.2  CF.sub.3                                  C C-(3-NH.sub.2)Ph     931     6-NMe.sub.2  CF.sub.3                                  C C-(2-NMe.sub.2)Ph     932     6-NMe.sub.2  CF.sub.3                                  C C-(3-NMe.sub.2)Ph     933     6-NMe.sub.2  CF.sub.3                                  C C-2-Pyridyl     934     6-NMe.sub.2  CF.sub.3                                  C C-3-Pyridyl     935     6-NMe.sub.2  CF.sub.3                                  C C-4-Pyridyl     936     6-NMe.sub.2  CF.sub.3                                  C C-2-furanyl     937     6-NMe.sub.2  CF.sub.3                                  C C-3-furanyl     938     6-NMe.sub.2  CF.sub.3                                  C C-2-thienyl     939     6-NMe.sub.2  CF.sub.3                                  C C-3-thienyl     940     6-NMe.sub.2  CF.sub.3                                  CHCH-cycPr     941     6-NMe.sub.2  CF.sub.3                                  CHCH-iPr     942     6-NMe.sub.2  CF.sub.3                                  CHCH-nPr     943     6-NMe.sub.2  CF.sub.3                                  CHCH-Bu     944     6-NMe.sub.2  CF.sub.3                                  CHCH-iBu     945     6-NMe.sub.2  CF.sub.3                                  CHCH-tBu     946     6-NMe.sub.2  CF.sub.3                                  CHCHEt     947     6-NMe.sub.2  CF.sub.3                                  CHCHMe     948     6-NMe.sub.2  CF.sub.3                                  CHCHPh     949     6-NMe.sub.2  CF.sub.3                                  CHCH-2-Pyridyl     950     6-NMe.sub.2  CF.sub.3                                  CHCH-3-Pyridyl     951     6-NMe.sub.2  CF.sub.3                                  CHCH-4-Pyridyl     952     6-NMe.sub.2  CF.sub.3                                  CHCH-2-furanyl     953     6-NMe.sub.2  CF.sub.3                                  CHCH-3-furanyl     954     6-NMe.sub.2  CF.sub.3                                  CHCH-2-thienyl     955     6-NMe.sub.2  CF.sub.3                                  CHCH-3-thienyl     956     6-NMe.sub.2  CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     957     6-NMe.sub.2  CF.sub.3                                  CH.sub.2 CH.sub.2 -cycPr     958     6-NMe.sub.2  CF.sub.3                                  CH.sub.2 CH.sub.2 -tBu     959     6-NMe.sub.2  CF.sub.3                                  CH.sub.2 CH.sub.2 Ph     960     6-NMe.sub.2  CF.sub.3                                  CH.sub.2 CH.sub.2 -2-Pyridyl     961     6-NMe.sub.2  CF.sub.3                                  CH.sub.2 CH.sub.2 -3-Pyridyl     962     6-NMe.sub.2  CF.sub.3                                  CH.sub.2 CH.sub.2 -4-Pyridyl     963     6-NMe.sub.2  CF.sub.3                                  CH.sub.2 CH.sub.2 -2-furanyl     964     6-NMe.sub.2  CF.sub.3                                  CH.sub.2 CH.sub.2 -3-furanyl     965     6-NMe.sub.2  CF.sub.3                                  CH.sub.2 CH.sub.2 -2-thienyl     966     6-NMe.sub.2  CF.sub.3                                  CH.sub.2 CH.sub.2 -3-thienyl     967     6-COCH.sub.3 CF.sub.3                                  C C-iPr     968     6-COCH.sub.3 CF.sub.3                                  C C-nPr     969     6-COCH.sub.3 CF.sub.3                                  C C-Bu     970     6-COCH.sub.3 CF.sub.3                                  C C-iBu     971     6-COCH.sub.3 CF.sub.3                                  C C-tBu     972     6-COCH.sub.3 CF.sub.3                                  C CMe     973     6-COCH.sub.3 CF.sub.3                                  C CPh     974     6-COCH.sub.3 CF.sub.3                                  C C-(2-Cl)Ph     975     6-COCH.sub.3 CF.sub.3                                  C C-(3-Cl)Ph     976     6-COCH.sub.3 CF.sub.3                                  C C-(2-F)Ph     977     6-COCH.sub.3 CF.sub.3                                  C C-(3-F)Ph     978     6-COCH.sub.3 CF.sub.3                                  C C-(2-OH)Ph     979     6-COCH.sub.3 CF.sub.3                                  C C-(3-OH)Ph     980     6-COCH.sub.3 CF.sub.3                                  C C-(2-OMe)Ph     981     6-COCH.sub.3 CF.sub.3                                  C C-(3-OMe)Ph     982     6-COCH.sub.3 CF.sub.3                                  C C-(2-CN)Ph     983     6-COCH.sub.3 CF.sub.3                                  C C-(3-CN)Ph     984     6-COCH.sub.3 CF.sub.3                                  C C-(2-NH.sub.2)Ph     985     6-COCH.sub.3 CF.sub.3                                  C C-(3-NH.sub.2)Ph     986     6-COCH.sub.3 CF.sub.3                                  C C-(2-NMe.sub.2)Ph     987     6-COCH.sub.3 CF.sub.3                                  C C-(3-NMe.sub.2)Ph     988     6-COCH.sub.3 CF.sub.3                                  C C-2-Pyridyl     989     6-COCH.sub.3 CF.sub.3                                  C C-3-Pyridyl     990     6-COCH.sub.3 CF.sub.3                                  C C-4-Pyridyl     991     6-COCH.sub.3 CF.sub.3                                  C C-2-furanyl     992     6-COCH.sub.3 CF.sub.3                                  C C-3-furanyl     993     6-COCH.sub.3 CF.sub.3                                  C C-2-thienyl     994     6-COCH.sub.3 CF.sub.3                                  C C-3-thienyl     995     6-COCH.sub.3 CF.sub.3                                  CHCH-cycPr     996     6-COCH.sub.3 CF.sub.3                                  CHCH-iPr     997     6-COCH.sub.3 CF.sub.3                                  CHCH-nPr     998     6-COCH.sub.3 CF.sub.3                                  CHCH-Bu     999     6-COCH.sub.3 CF.sub.3                                  CHCH-iBu     1000    6-COCH.sub.3 CF.sub.3                                  CHCH-tBu     1001    6-COCH.sub.3 CF.sub.3                                  CHCHEt     1002    6-COCH.sub.3 CF.sub.3                                  CHCHMe     1003    6-COCH.sub.3 CF.sub.3                                  CHCHPh     1004    6-COCH.sub.3 CF.sub.3                                  CHCH-2-Pyridyl     1005    6-COCH.sub.3 CF.sub.3                                  CHCH-3-Pyridyl     1006    6-COCH.sub.3 CF.sub.3                                  CHCH-4-Pyridyl     1007    6-COCH.sub.3 CF.sub.3                                  CHCH-2-furanyl     1008    6-COCH.sub.3 CF.sub.3                                  CHCH-3-furanyl     1009    6-COCH.sub.3 CF.sub.3                                  CHCH-2-thienyl     1010    6-COCH.sub.3 CF.sub.3                                  CHCH-3-thienyl     1011    6-COCH.sub.3 CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                  N     1012    6-COCH.sub.3 CF.sub.3                                  CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2     1013    6-COCH.sub.3 CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     1014    6-COCH.sub.3 CF.sub.3                                  CH.sub.2 CH.sub.2 -cycPr     1015    6-COCH.sub.3 CF.sub.3                                  CH.sub.2 CH.sub.2 -tBu     1016    6-COCH.sub.3 CF.sub.3                                  CH.sub.2 CH.sub.2 Ph     1017    6-COCH.sub.3 CF.sub.3                                  CH.sub.2 CH.sub.2 -2-Pyridyl     1018    6-COCH.sub.3 CF.sub.3                                  CH.sub.2 CH.sub.2 -3-Pyridyl     1019    6-COCH.sub.3 CF.sub.3                                  CH.sub.2 CH.sub.2 -4-Pyridyl     1020    6-COCH.sub.3 CF.sub.3                                  CH.sub.2 CH.sub.2 -2-furanyl     1021    6-COCH.sub.3 CF.sub.3                                  CH.sub.2 CH.sub.2 -3-furanyl     1022    6-COCH.sub.3 CF.sub.3                                  CH.sub.2 CH.sub.2 -2-thienyl     1023    6-COCH.sub.3 CF.sub.3                                  CH.sub.2 CH.sub.2 -3-thienyl     1024    6-CH.sub.3   CF.sub.3                                  C C-nPr     1025    6-CH.sub.3   CF.sub.3                                  C C-Bu     1026    6-CH.sub.3   CF.sub.3                                  C C-iBu     1027    6-CH.sub.3   CF.sub.3                                  C C-tBu     1028    6-CH.sub.3   CF.sub.3                                  C CMe     1029    6-CH.sub.3   CF.sub.3                                  C CPh     1030    6-CH.sub.3   CF.sub.3                                  C C-(2-Cl)Ph     1031    6-CH.sub.3   CF.sub.3                                  C C-(3-Cl)Ph     1032    6-CH.sub.3   CF.sub.3                                  C C-(2-F)Ph     1033    6-CH.sub.3   CF.sub.3                                  C C-(3-F)Ph     1034    6-CH.sub.3   CF.sub.3                                  C C-(2-OH)Ph     1035    6-CH.sub.3   CF.sub.3                                  C C-(3-OH)Ph     1036    6-CH.sub.3   CF.sub.3                                  C C-(2-OMe)Ph     1037    6-CH.sub.3   CF.sub.3                                  C C-(3-OMe)Ph     1038    6-CH.sub.3   CF.sub.3                                  C C-(2-CN)Ph     1039    6-CH.sub.3   CF.sub.3                                  C C-(3-CN)Ph     1040    6-CH.sub.3   CF.sub.3                                  C C-(2-NH.sub.2)Ph     1041    6-CH.sub.3   CF.sub.3                                  C C-(3-NH.sub.2)Ph     1042    6-CH.sub.3   CF.sub.3                                  C C-(2-NMe.sub.2)Ph     1043    6-CH.sub.3   CF.sub.3                                  C C-(3-NMe.sub.2)Ph     1044    6-CH.sub.3   CF.sub.3                                  C C-2-Pyridyl     1045    6-CH.sub.3   CF.sub.3                                  C C-3-Pyridyl     1046    6-CH.sub.3   CF.sub.3                                  C C-4-Pyridyl     1047    6-CH.sub.3   CF.sub.3                                  C C-2-furanyl     1048    6-CH.sub.3   CF.sub.3                                  C C-3-furanyl     1049    6-CH.sub.3   CF.sub.3                                  C C-2-thienyl     1050    6-CH.sub.3   CF.sub.3                                  C C-3-thienyl     1051    6-CH.sub.3   CF.sub.3                                  CHCH-cycPr     1052    6-CH.sub.3   CF.sub.3                                  CHCH-iPr     1053    6-CH.sub.3   CF.sub.3                                  CHCH-nPr     1054    6-CH.sub.3   CF.sub.3                                  CHCH-Bu     1055    6-CH.sub.3   CF.sub.3                                  CHCH-iBu     1056    6-CH.sub.3   CF.sub.3                                  CHCH-tBu     1057    6-CH.sub.3   CF.sub.3                                  CHCHEt     1058    6-CH.sub.3   CF.sub.3                                  CHCHMe     1059    6-CH.sub.3   CF.sub.3                                  CHCHPh     1060    6-CH.sub.3   CF.sub.3                                  CHCH-2-Pyridyl     1061    6-CH.sub.3   CF.sub.3                                  CHCH-3-Pyridyl     1062    6-CH.sub.3   CF.sub.3                                  CHCH-4-Pyridyl     1063    6-CH.sub.3   CF.sub.3                                  CHCH-2-furanyl     1064    6-CH.sub.3   CF.sub.3                                  CHCH-3-furanyl     1065    6-CH.sub.3   CF.sub.3                                  CHCH-2-thienyl     1066    6-CH.sub.3   CF.sub.3                                  CHCH-3-thienyl     1067    6-CH.sub.3   CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                  N     1068    6-CH.sub.3   CF.sub.3                                  CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2     1069    6-CH.sub.3   CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     1070    6-CH.sub.3   CF.sub.3                                  CH.sub.2 CH.sub.2 -cycPr     1071    6-CH.sub.3   CF.sub.3                                  CH.sub.2 CH.sub.2 -tBu     1072    6-CH.sub.3   CF.sub.3                                  CH.sub.2 CH.sub.2 -Ph     1073    6-CH.sub.3   CF.sub.3                                  CH.sub.2 CH.sub.2 -2-Pyridyl     1074    6-CH.sub.3   CF.sub.3                                  CH.sub.2 CH.sub.2 -3-Pyridyl     1075    6-CH.sub.3   CF.sub.3                                  CH.sub.2 CH.sub.2 -4-Pyridyl     1076    6-CH.sub.3   CF.sub.3                                  CH.sub.2 CH.sub.2 -2-furanyl     1077    6-CH.sub.3   CF.sub.3                                  CH.sub.2 CH.sub.2 -3-furanyl     1078    6-CH.sub.3   CF.sub.3                                  CH.sub.2 CH.sub.2 -2-thienyl     1079    6-CH.sub.3   CF.sub.3                                  CH.sub.2 CH.sub.2 -3-thienyl     1080    6,8-diCl     CF.sub.3                                  C C-iPr     1081    6,8-diCl     CF.sub.3                                  C C-nPr     1082    6,8-diCl     CF.sub.3                                  C CEt     1083    6,8-diCl     CF.sub.3                                  C CMe     1084    6,8-diCl     CF.sub.3                                  C CPh     1085    6,8-diCl     CF.sub.3                                  C C-2-Pyridyl     1086    6,8-diCl     CF.sub.3                                  C C-3-Pyridyl     1087    6,8-diCl     CF.sub.3                                  C C-4-Pyridyl     1088    6,8-diCl     CF.sub.3                                  C C-2-furanyl     1089    6,8-diCl     CF.sub.3                                  C C-3-furanyl     1090    6,8-diCl     CF.sub.3                                  C C-2-thienyl     1091    6,8-diCl     CF.sub.3                                  C C-3-thienyl     1092    6,8-diCl     CF.sub.3                                  CHCH-cycPr     1093    6,8-diCl     CF.sub.3                                  CHCH-iPr     1094    6,8-diCl     CF.sub.3                                  CHCH-nPr     1095    6,8-diCl     CF.sub.3                                  CHCHEt     1096    6,8-diCl     CF.sub.3                                  CHCHMe     1097    6,8-diCl     CF.sub.3                                  CHCHPh     1098    6,8-diCl     CF.sub.3                                  CHCH-2-Pyridyl     1099    6,8-diCl     CF.sub.3                                  CHCH-3-Pyridyl     1100    6,8-diCl     CF.sub.3                                  CHCH-4-Pyridyl     1101    6,8-diCl     CF.sub.3                                  CHCH-2-furanyl     1102    6,8-diCl     CF.sub.3                                  CHCH-3-furanyl     1103    6,8-diCl     CF.sub.3                                  CHCH-2-thienyl     1104    6,8-diCl     CF.sub.3                                  CHCH-3-thienyl     1105    6,8-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                  O     1106    6,8-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2     1107    6,8-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     1108    6,8-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 -cycPr     1109    6,8-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 -2-Pyridyl     1110    6,8-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 -3-Pyridyl     1111    6,8-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 -4-Pyridyl     1112    6,8-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 -2-furanyl     1113    6,8-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 -3-furanyl     1114    6,8-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 -2-thienyl     1115    6,8-diCl     CF.sub.3                                  CH.sub.2 CH.sub.2 -3-thienyl     1116    5,6,8-triF   CF.sub.3                                  C CMe     1117    5,6,8-triF   CF.sub.3                                  C CPh     1118    5,6,8-triF   CF.sub.3                                  C C-2-Pyridyl     1119    5,6,8-triF   CF.sub.3                                  C C-3-Pyridyl     1120    5,6,8-triF   CF.sub.3                                  C C-4-Pyridyl     1121    5,6,8-triF   CF.sub.3                                  C C-2-furanyl     1122    5,6,8-triF   CF.sub.3                                  C C-3-furanyl     1123    5,6,8-triF   CF.sub.3                                  C C-2-thienyl     1124    5,6,8-triF   CF.sub.3                                  C C-3-thienyl     1125    5,6,8-triF   CF.sub.3                                  CHCH-cycPr     1126    5,6,8-triF   CF.sub.3                                  CHCH-iPr     1127    5,6,8-triF   CF.sub.3                                  CHCH-nPr     1128    5,6,8-triF   CF.sub.3                                  CHCHEt     1129    5,6,8-triF   CF.sub.3                                  CHCHMe     1130    5,6,8-triF   CF.sub.3                                  CHCHPh     1131    5,6,8-triF   CF.sub.3                                  CHCH-2-Pyridyl     1132    5,6,8-triF   CF.sub.3                                  CHCH-3-Pyridyl     1133    5,6,8-triF   CF.sub.3                                  CHCH-4-Pyridyl     1134    5,6,8-triF   CF.sub.3                                  CHCH-2-furanyl     1135    5,6,8-triF   CF.sub.3                                  CHCH-3-furanyl     1136    5,6,8-triF   CF.sub.3                                  CHCH-2-thienyl     1137    5,6,8-triF   CF.sub.3                                  CHCH-3-thienyl     1138    5,6,8-triF   CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                  N     1139    5,6,8-triF   CF.sub.3                                  CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2     1140    5,6,8-triF   CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     1141    5,6,8-triF   CF.sub.3                                  CH.sub.2 CH.sub.2 -cycPr     1142    5,6,8-triF   CF.sub.3                                  CH.sub.2 CH.sub.2 Ph     1143    5,618-triF   CF.sub.3                                  CH.sub.2 CH.sub.2 -2-Pyridyl     1144    5,6,8-triF   CF.sub.3                                  CH.sub.2 CH.sub.2 -3-Pyridyl     1145    5,6,8-triF   CF.sub.3                                  CH.sub.2 CH.sub.2 -4-Pyridyl     1146    5,6,8-triF   CF.sub.3                                  CH.sub.2 CH.sub.2 -2-furanyl     1147    5,6,8-triF   CF.sub.3                                  CH.sub.2 CH.sub.2 -3-furanyl     1148    5,6,8-triF   CF.sub.3                                  CH.sub.2 CH.sub.2 -2-thienyl     1149    5,6,8-triF   CF.sub.3                                  CH.sub.2 CH.sub.2 -3-thienyl     1150    5,8-diF      CF.sub.3                                  C CMe     1151    5,8-diF      CF.sub.3                                  C CPh     1152    5,8-diF      CF.sub.3                                  C C-2-Pyridyl     1153    5,8-diF      CF.sub.3                                  C C-3-Pyridyl     1154    5,8-diF      CF.sub.3                                  C C-4-Pyridyl     1155    5,8-diF      CF.sub.3                                  C C-2-furanyl     1156    5,8-diF      CF.sub.3                                  C C-3-furanyl     1157    5,8-diF      CF.sub.3                                  C C-2-thienyl     1158    5,8-diF      CF.sub.3                                  C C-3-thienyl     1159    5,8-diF      CF.sub.3                                  CHCH-cycPr     1160    5,8-diF      CF.sub.3                                  CHCH-iPr     1161    5,8-diF      CF.sub.3                                  CHCH-nPr     1162    5,8-diF      CF.sub.3                                  CHCHEt     1163    5,8-diF      CF.sub.3                                  CHCHMe     1164    5,8-diF      CF.sub.3                                  CHCHPh     1165    5,8-diF      CF.sub.3                                  CHCH-2-Pyridyl     1166    5,8-diF      CF.sub.3                                  CHCH-3-Pyridyl     1167    5,8-diF      CF.sub.3                                  CHCH-4-Pyridyl     1168    5,8-diF      CF.sub.3                                  CHCH-2-furanyl     1169    5,8-diF      CF.sub.3                                  CHCH-3-furanyl     1170    5,8-diF      CF.sub.3                                  CHCH-2-thienyl     1171    5,8-diF      CF.sub.3                                  CHCH-3-thi-enyl     1172    5,8-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                  N     1173    5,8-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2     1174    5,8-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     1175    5,8-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -cycPr     1176    5,8-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -Ph     1177    5,8-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -2-Pyridyl     1178    5,8-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -3-Pyridyl     1179    5,8-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -4-Pyridyl     1180    5,8-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -2-furanyl     1131    5,8-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -3-furanyl     1182    5,8-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -2-thienyl     1183    5,8-diF      CF.sub.3                                  CH.sub.2 CH.sub.2 -3-thienyl     1184    6-iPr        CF.sub.3                                  C C-nPr     1185    6-iPr        CF.sub.3                                  C CEt     1186    6-iPr        CF.sub.3                                  C CMe     1187    6-iPr        CF.sub.3                                  C C-3-Pyridyl     1188    6-iPr        CF.sub.3                                  C C-2-furanyl     1189    6-iPr        CF.sub.3                                  C C-3-furanyl     1190    6-iPr        CF.sub.3                                  C C-2-thienyl     1191    6-iPr        CF.sub.3                                  C C-3-thienyl     1192    6-iPr        CF.sub.3                                  CHCH-cycPr     1193    6-iPr        CF.sub.3                                  CHCH-iPr     1194    6-iPr        CF.sub.3                                  CHCH-nPr     1195    6-iPr        CF.sub.3                                  CHCHEt     1196    6-iPr        CF.sub.3                                  CHCHMe     1197    6-iPr        CF.sub.3                                  CHCHPh     1198    6-iPr        CF.sub.3                                  CHCH-2-furanyl     1199    6-iPr        CF.sub.3                                  CHCH-3-furanyl     1200    6-iPr        CF.sub.3                                  CHCH-2-thienyl     1201    6-iPr        CF.sub.3                                  CHCH-3-thienyl     1202    6-iPr        CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     1203    6-iPr        CF.sub.3                                  CH.sub.2 CH.sub.2 -cycPr     1204    6-OCF.sub.3  CF.sub.3                                  C C-nPr     1205    6-OCF.sub.3  CF.sub.3                                  C C-Et     1206    6-OCF.sub.3  CF.sub.3                                  C C-Me     1207    6-OCF.sub.3  CF.sub.3                                  C C-3-Pyridyl     1208    6-OCF.sub.3  CF.sub.3                                  C C-2-furanyl     1209    6-OCF.sub.3  CF.sub.3                                  C C-3-furanyl     1210    6-CCF.sub.3  CF.sub.3                                  C C-2-thienyl     1211    6-OCF.sub.3  CF.sub.3                                  C C-3-thienyl     1212    6-OCF.sub.3  CF.sub.3                                  CHCH-cycPr     1213    6-OCF.sub.3  CF.sub.3                                  CHCH-iPr     1214    6-OCF.sub.3  CF.sub.3                                  CHCH-nPr     1215    6-OCF.sub.3  CF.sub.3                                  CHCH-Et     1216    6-OCF.sub.3  CF.sub.3                                  CHCH-Me     1217    6-OCF.sub.3  CF.sub.3                                  CHCH-Ph     1218    6-OCF.sub.3  CF.sub.3                                  CHCH-3-Pyridyl     1219    6-OCF.sub.3  CF.sub.3                                  CHCH-2-furanyl     1220    6-OCF.sub.3  CF.sub.3                                  CHCH-3-furanyl     1221    6-OCF.sub.3  CF.sub.3                                  CHCH-2-thienyl     1222    6-OCF.sub.3  CF.sub.3                                  CHCH-3-thienyl     1223    6-OCF.sub.3  CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     1224    6-OCF.sub.3  CF.sub.3                                  CH.sub.2 CH.sub.2 -cycPr     1225    6-(pyrazol-5-yl)                          CF.sub.3                                  C C-cycPr     1226    6-(pyrazol-5-yl)                          CF.sub.3                                  C C-iPr     1227    6-(pyrazol-5-yl)                          CF.sub.3                                  C C-nPr     1228    6-(pyrazol-5-yl)                          CF.sub.3                                  C C-Et     1229    6-(pyrazol-5-yl)                          CF.sub.3                                  C C-Me     1230    6-(pyrazol-5-yl)                          CF.sub.3                                  C C-Ph     1231    6-(pyrazol-5-yl)                          CF.sub.3                                  C C-3-Pyridyl     1232    6-(pyrazol-5-yl)                          CF.sub.3                                  C C-2-furanyl     1233    6-(pyrazol-5-yl)                          CF.sub.3                                  C C-3-furanyl     1234    6-(pyrazol-5-yl)                          CF.sub.3                                  C C-2-thienyl     1235    6-(pyrazol-5-yl)                          CF.sub.3                                  C C-3-thienyl     1236    6-(pyrazol-5-yl)                          CF.sub.3                                  CHCH-cycPr     1237    6-(pyrazol-5-yl)                          CF.sub.3                                  CHCH-iPr     1238    6-(pyrazol-5-yl)                          CF.sub.3                                  CHCH-nPr     1239    6-(pyrazol-5-yl)                          CF.sub.3                                  CHCHEt     1240    6-(pyrazol-5-yl)                          CF.sub.3                                  CHCHMe     1241    6-(pyrazol-5-yl)                          CF.sub.3                                  CHCHPh     1242    6-(pyrazol-5-yl)                          CF.sub.3                                  CHCH-3-Pyridyl     1243    6-(pyrazol-5-yl)                          CF.sub.3                                  CHCH-2-furanyl     1244    6-(pyrazol-5-yl)                          CF.sub.3                                  CHCH-3-furanyl     1245    6-(pyrazol-5-yl)                          CF.sub.3                                  CHCH-2-thienyl     1246    6-(pyrazol-5-yl)                          CF.sub.3                                  CHCH-3-thienyl     1247    6-(pyrazol-5-yl)                          CF.sub.3                                  Pentyl     1248    6-(pyrazol-5-yl)                          CF.sub.3                                  CH.sub.2 CH.sub.2 -iPr     1249    6-(pyrazol-5-yl)                          CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     1250    6-(pyrazol-5-yl)                          CF.sub.3                                  CH.sub.2 CH.sub.2 -cycPr     1251    H            CF.sub.3                                  C C-nPr     1252    H            CF.sub.3                                  C CEt     1253    H            CF.sub.3                                  C CMe     1254    H            CF.sub.3                                  C C-3-Pyridyl     1255    H            CF.sub.3                                  C C-2-furanyl     1256    H            CF.sub.3                                  C C-3-furanyl     1257    H            CF.sub.3                                  C C-2-thienyl     1258    H            CF.sub.3                                  C C-3-thienyl     1259    H            CF.sub.3                                  CHCH-cycPr     1260    H            CF.sub.3                                  CHCH-iPr     1261    H            CF.sub.3                                  CHCH-nPr     1262    H            CF.sub.3                                  CHCHEt     1263    H            CF.sub.3                                  CHCHMe     1264    H            CF.sub.3                                  CHCHPh     1265    H            CF.sub.3                                  CHCH-3-Pyridyl     1266    H            CF.sub.3                                  CHCH-2-furanyl     1267    H            CF.sub.3                                  CHCH-3-furanyl     1268    H            CF.sub.3                                  CHCH-2-thienyl     1269    H            CF.sub.3                                  CHCH-3-thienyl     1270    H            CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     1271    H            CF.sub.3                                  CH.sub.2 CH.sub.2 -cycPr     1272    6-Ph         CF.sub.3                                  C CMe     1273    6-Ph         CF.sub.3                                  C CPh     1274    6-Ph         CF.sub.3                                  C C-3-Pyridyl     1275    6-Ph         CF.sub.3                                  C C-2-furanyl     1276    6-Ph         CF.sub.3                                  C C-3-furanyl     1277    6-Ph         CF.sub.3                                  C C-2-thienyl     1278    6-Ph         CF.sub.3                                  C C-3-thienyl     1279    6-Ph         CF.sub.3                                  CHCH-cycPr     1280    6-Ph         CF.sub.3                                  CHCH-iPr     1281    6-Ph         CF.sub.3                                  CHCH-nPr     1282    6-Ph         CF.sub.3                                  CHCHEt     1283    6-Ph         CF.sub.3                                  CHCHMe     1284    6-Ph         CF.sub.3                                  CHCHPh     1285    6-Ph         CF.sub.3                                  CHCH-3-Pyridyl     1286    6-Ph         CF.sub.3                                  CHCH-2-furanyl     1287    6-Ph         CF.sub.3                                  CHCH-3-furanyl     1288    6-Ph         CF.sub.3                                  CHCH-2-thienyl     1289    6-Ph         CF.sub.3                                  CHCH-3-thienyl     1290    6-Ph         CF.sub.3                                  Pentyl     1291    6-Ph         CF.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     1292    6-Ph         CF.sub.3                                  CH.sub.2 CH.sub.2 -cycPr     1293    6-CN         CF.sub.3                                  C C-cycPr     1294    6-CN         CF.sub.3                                  C C-iPr     1295    6-CN         CF.sub.3                                  C C-nPr     1296    6-CN         CF.sub.3                                  C C-Et     1297    6-CN         CF.sub.3                                  C C-3-Pyridyl     1298    6-CN         CF.sub.3                                  C C-2-furanyl     1299    6-CN         CF.sub.3                                  C C-3-furanyl     1300    6-CN         CF.sub.3                                  C C-2-thienyl     1301    6-CN         CF.sub.3                                  C C-3-thienyl     1302    6-CN         CF.sub.3                                  CHCH-cycPr     1303    6-CN         CF.sub.3                                  CHCH-iPr     1304    6-CN         CF.sub.3                                  CHCH-nPr     1305    6-CN         CF.sub.3                                  CHCH-Bt     1306    6-CN         CF.sub.3                                  CHCH-3-Pyridyl     1307    6-CN         CF.sub.3                                  CHCH-2-furanyl     1308    6-CN         CF.sub.3                                  CHCH-3-furanyl     1309    6-CN         CF.sub.3                                  CHCH-2-thienyl     1310    6-CN         CF.sub.3                                  CHCH-3-thienyl     1311    6-NO.sub.2   CF.sub.3                                  C C-cycPr     1312    6-NO.sub.2   CF.sub.3                                  C C-iPr     1313    6-NO.sub.2   CF.sub.3                                  C C-nPr     1314    6-NO.sub.2   CF.sub.3                                  C C-Et     1315    6-NO.sub.2   CF.sub.3                                  C C-3-Pyridyl     1316    6-NO.sub.2   CF.sub.3                                  C C-2-furanyl     1317    6-NO.sub.2   CF.sub.3                                  C C-3-furanyl     1318    6-NO.sub.2   CF.sub.3                                  C C-2-thienyl     1319    6-NO.sub.2   CF.sub.3                                  C C-3-thienyl     1320    6-NHMe       CF.sub.3                                  C C-cycPr     1321    6-NHMe       CF.sub.3                                  C C-iPr     1322    6-NHMe       CF.sub.3                                  C C-nPr     1323    6-NHMe       CF.sub.3                                  C C-Et     1324    6-NHMe       CF.sub.3                                  C C-3-Pyridyl     1325    6-NHMe       CF.sub.3                                  C C-2-furanyl     1326    6-NHMe       CF.sub.3                                  C C-3-furanyl     1327    6-NHMe       CF.sub.3                                  C C-2-thienyl     1328    6-NHMe       CF.sub.3                                  C C-3-thienyl     1329    6-NHMe       CF.sub.3                                  CHCH-cycPr     1330    6-NHMe       CF.sub.3                                  CHCH-iPr     1331    6-NHMe       CF.sub.3                                  CHCH-nPr     1332    6-NHMe       CF.sub.3                                  CHCH-Et     1333    6-NHMe       CF.sub.3                                  CHCH-3-Pyridyl     1334    6-NHMe       CF.sub.3                                  CHCH-2-furanyl     1335    6-NHMe       CF.sub.3                                  CHCH-3-furanyl     1336    6-NHMe       CF.sub.3                                  CHCH-2-thienyl     1337    6-NHMe       CF.sub.3                                  CHCH-3-thienyl     1338    6,7-OCH.sub.2 O                          CF.sub.3                                  C C-cycPr     1339    6,7-OCH.sub.2 O                          CF.sub.3                                  C C-iPr     1340    6,7-OCH.sub.2 O                          CF.sub.3                                  C C-nPr     1341    6,7-OCH.sub.2 O                          CF.sub.3                                  C C-Et     1342    6,7-OCH.sub.2 O                          CF.sub.3                                  C C-3-Pyridyl     1343    6,7-OCH.sub.2 O                          CF.sub.3                                  C C-2-furanyl     1344    6,7-OCH.sub.2 O                          CF.sub.3                                  C C-3-furanyl     1345    6,7-OCH.sub.2 O                          CF.sub.3                                  C C-2-thienyl     1346    6,7-OCH.sub.2 O                          CF.sub.3                                  C C-3-thienyl     1347    6,7-diCl     CF.sub.3                                  C C-cycPr     1348    6,7-diCl     CF.sub.3                                  C C-iPr     1349    6,7-diCl     CF.sub.3                                  C C-nPr     1350    6,7-diCl     CF.sub.3                                  C C-Et     1351    6,7-diCl     CF.sub.3                                  C C-3-Pyridyl     1352    6,7-diCl     CF.sub.3                                  C C-2-furanyl     1353    6,7-diCl     CF.sub.3                                  C C-3-furanyl     1354    6,7-diCl     CF.sub.3                                  C C-2-thienyl     1355    6,7-diCl     CF.sub.3                                  C C-3-thienyl     1356    7-Cl         CF.sub.3                                  C C-cycPr     1357    7-Cl         CF.sub.3                                  C C-iPr     1358    7-Cl         CF.sub.3                                  C C-nPr     1359    7-Cl         CF.sub.3                                  C C-Et     1360    7-Cl         CF.sub.3                                  C C-3-Pyridyl     1361    7-Cl         CF.sub.3                                  C C-2-furanyl     1362    7-Cl         CF.sub.3                                  C C-3-furanyl     1363    7-Cl         CF.sub.3                                  C C-2-thienyl     1364    7-Cl         CF.sub.3                                  C C-3-thienyl     ______________________________________      *Unless otherwise noted, stereochemistry is (+/-).

                  TABLE 3     ______________________________________      ##STR44##     Ex. #   G            R.sup.1 R.sup.2     ______________________________________     1401    6-Cl, 8-F    cycPr   C C-cycPr     1402    6-Cl, 8-F    cycPr   C C-iPr     1403    6-Cl, 8-F    cycPr   C C-nPr     1404    6-Cl, 8-F    cycPr   C C-Et     1405    6-Cl, 8-F    cycPr   C C-3-Pyridyl     1406    6-Cl, 8-F    cycPr   C C-2-furanyl     1407    6-Cl, 8-F    cycPr   C C-3-furanyl     1408    6-Cl, 8-F    cycPr   C C-2-thienyl     1409    6-Cl, 8-F    cycPr   C C-3-thienyl     1410    6-Cl, 8-F    iPr     C C-cycPr     1411    6-Cl, 8-F    iPr     C C-iPr     1412    6-Cl, 8-F    iPr     C C-nPr     1413    6-Cl, 8-F    iPr     C C-Et     1414    6-Cl, 8-F    iPr     C C-3-Pyridyl     1415    6-Cl, 8-F    iPr     C C-2-furanyl     1416    6-Cl, 8-F    iPr     C C-3-furanyl     1417    6-Cl, 8-F    iPr     C C-2-thienyl     1418    6-Cl, 8-F    iPr     C C-3-thienyl     1419    6-Cl, 8-F    Et      C C-cycPr     1420    6-Cl, 8-F    Et      C C-iPr     1421    6-Cl, 8-F    Et      C C-nPr     1422    6-Cl, 8-F    Et      C C-Et     1423    5,6-diF      cycPr   C C-cycPr     1424    5,6-diF      cycPr   C C-iPr     1425    5,6-diF      cycPr   C C-nPr     1426    5,6-diF      cycPr   C C-Et     1427    5,6-diF      cycPr   C C-3-Pyridyl     1428    5,6-diF      cycPr   C C-2-furanyl     1429    5,6-diF      cycPr   C C-3-furanyl     1430    5,6-diF      cycPr   C C-2-thienyl     1431    5,6-diF      cycPr   C C-3-thienyl     1432    5,6-diF      iPr     C C-cycPr     1433    5,6-diF      iPr     C C-iPr     1434    5,6-diF      iPr     C C-nPr     1435    5,6-diF      iPr     C C-Et     1436    5,6-diF      iPr     C C-3-Pyridyl     1437    5,6-diF      iPr     C C-2-furanyl     1438    5,6-diF      iPr     C C-3-furanyl     1439    5,6-diF      iPr     C C-2-thienyl     1440    5,6-diF      iPr     C C-3-thienyl     1441    5,6-diF      Et      C C-cycPr     1442    5,6-diF      Et      C C-iPr     1443    5,6-dip      Et      C C-nPr     1444    5,6-diF      Et      C C-Et     1445    5,6-diCl     cycPr   C C-cycPr     1446    5,6-diCl     cycPr   C C-iPr     1447    5,6-diCl     cycPr   C C-nPr     1448    5,6-diCl     cycPr   C C-Et     1449    5,6-diCl     cycPr   C C-3-Pyridyl     1450    5,6-diCl     cycPr   C C-2-furanyl     1451    5,6-diCl     cycPr   C C-3-furanyl     1452    5,6-diCl     cycPr   C C-2-thienyl     1453    5,6-diCl     cycPr   C C-3-thienyl     1454    5,6-diCl     iPr     C C-cycPr     1455    5,6-diCl     iPr     C C-iPr     1456    5,6-diCl     iPr     C C-nPr     1457    5,6-diCl     iPr     C C-Et     1458    5,6-diCl     iPr     C C-3-Pyridyl     1459    5,6-diCl     iPr     C C-2-furanyl     1460    5,6-diCl     iPr     C C-3-furanyl     1461    5,6-diCl     iPr     C C-2-thienyl     1462    5,6-diCl     iPr     C C-3-thienyl     1463    5,6-diCl     Et      C C-cycPr     1464    5,6-diCl     Et      C C-iPr     1465    5,6-diCl     Et      C C-nPr     1466    5,6-diCl     Et      C C-Et     1467    5-Cl,6-F     cycPr   C C-cycPr     1468    5-Cl,6-F     cycPr   C C-iPr     1469    5-Cl,6-F     cycPr   C C-nPr     1470    5-Cl,6-F     cycPr   C C-Et     1471    5-Cl,6-F     cycPr   C C-3-Pyridyl     1472    5-Cl,6-F     cycPr   C C-2-furanyl     1473    5-Cl,6-F     cycPr   C C-3-furanyl     1474    5-Cl,6-F     cycPr   C C-2-thienyl     1475    5-Cl,6-F     cycPr   C C-3-thienyl     1476    5-Cl,6-F     iPr     C C-cycPr     1477    5-Cl,6-F     iPr     C C-iPr     1478    5-Cl,6-F     iPr     C C-nPr     1479    5-Cl,6-F     iPr     C C-Et     1480    5-Cl,6-F     iPr     C C-3-Pyridyl     1481    5-Cl,6-F     iPr     C C-2-furanyl     1482    5-Cl,6-F     iPr     C C-3-furanyl     1483    5-Cl,6-F     iPr     C C-2-thienyl     1484    5-Cl,6-F     iPr     C C-3-thienyl     1485    5-Cl,6-F     Et      C C-cycPr     1486    5-Cl,6-F     Et      C C-iPr     1487    5-Cl,6-F     Et      C C-nPr     1488    5-Cl,6-F     Et      C C-Et     1489    5,6-OCH.sub.2 O                          cycPr   C C-cycPr     1490    5,6-OCH.sub.2 O                          cycPr   C C-iPr     1491    5,6-OCH.sub.2 O                          cycPr   C C-nPr     1492    5,6-OCH.sub.2 O                          cycPr   C C-Et     1493    5,6-OCH.sub.2 O                          cycPr   C C-3-Pyridyl     1494    5,6-OCH.sub.2 O                          cycPr   C C-2-furanyl     1495    5,6-OCH.sub.2 O                          cycPr   C C-3-furanyl     1496    5,6-OCH.sub.2 O                          cycPr   C C-2-thienyl     1497    5,6-OCH.sub.2 O                          cycPr   C C-3-thienyl     1498    5,6-OCH.sub.2 O                          iPr     C C-cycPr     1499    5,6-OCH.sub.2 O                          iPr     C C-iPr     1500    5,6-OCH.sub.2 O                          iPr     C C-nPr     1501    5,6-OCH.sub.2 O                          iPr     C C-Et     1502    5,6-OCH.sub.2 O                          iPr     C C-3-Pyridyl     1503    5,6-OCH.sub.2 O                          iPr     C C-2-furanyl     1504    5,6-OCH.sub.2 O                          iPr     C C-3-furanyl     1505    5,6-OCH.sub.2 O                          iPr     C C-2-thienyl     1506    5,6-OCH.sub.2 O                          iPr     C C-3-thienyl     1507    5,6-OCH.sub.2 O                          Et      C C-cycPr     1508    5,6-OCH.sub.2 O                          Et      C C-iPr     1509    5,6-OCH.sub.2 O                          Et      C C-nPr     1510    5,6-OCH.sub.2 O                          Et      C C-Et     1511    5-F          cycPr   C C-cycPr     1512    5-F          cycPr   C C-iPr     1513    5-F          cycPr   C C-nPr     1514    5-F          cycPr   C C-Et     1515    5-F          cycPr   C C-3-Pyridyl     1516    5-F          cycPr   C C-2-furanyl     1517    5-F          cycPr   C C-3-furanyl     1518    5-F          cycPr   C C-2-thienyl     1519    5-F          cycPr   C C-3-thienyl     1520    5-F          iPr     C C-cycPr     1521    5-F          iPr     C C-iPr     1522    5-F          iPr     C C-nPr     1523    5-F          iPr     C C-Et     1524    5-F          iPr     C C-3-Pyridyl     1525    5-F          iPr     C C-2-furanyl     1526    5-F          iPr     C C-3-furanyl     1527    5-F          iPr     C C-2-thienyl     1528    5-F          iPr     C C-3-thienyl     1529    5-F          Et      C C-cycPr     1530    5-F          Et      C C-iPr     1531    5-F          Et      C C-nPr     1532    5-F          Et      C C-Et     1533    5-Cl         cycPr   C C-cycPr     1534    5-Cl         cycPr   C C-iPr     1535    5-Cl         cycPr   C C-nPr     1536    5-Cl         cycPr   C C-Et     1537    5-Cl         cycPr   C C-3-Pyridyl     1538    5-Cl         cycPr   C C-2-furanyl     1539    5-Cl         cycPr   C C-3-furanyl     1540    5-Cl         cycPr   C C-2-thienyl     1541    5-Cl         cycPr   C C-3-thienyl     1542    5-Cl         iPr     C C-cycPr     1543    5-Cl         iPr     C C-iPr     1544    5-Cl         iPr     C C-nPr     1545    5-Cl         iPr     C C-Et     1546    5-Cl         iPr     C C-3-Pyridyl     1547    5-Cl         iPr     C C-2-furanyl     1548    5-Cl         iPr     C C-3-furanyl     1549    5-Cl         iPr     C C-2-thienyl     1550    5-Cl         iPr     C C-3-thienyl     1551    5-Cl         Et      C C-cycPr     1552    5-Cl         Et      C C-iPr     1553    5-Cl         Et      C C-nPr     1554    5-Cl         Et      C C-Et     1555    6-OMe        cycPr   C C-cycPr     1556    6-OMe        cycPr   C C-iPr     1557    6-OMe        cycPr   C C-nPr     1558    6-OMe        cycPr   C C-Et     1559    6-OMe        cycPr   C C-3-Pyridyl     1560    6-OMe        cycPr   C C-2-furanyl     1561    6-OMe        cycPr   C C-3-furanyl     1562    6-OMe        cycPr   C C-2-thienyl     1563    6-OMe        cycPr   C C-3-thienyl     1564    6-OMe        iPr     C C-nPr     1565    6-OMe        iPr     C C-Et     1566    6-OMe        iPr     C C-3-Pyridyl     1567    6-OMe        iPr     C C-2-furanyl     1568    6-OMe        iPr     C C-3-furanyl     1569    6-OMe        iPr     C C-2-thienyl     1570    6-OMe        iPr     C C-3-thienyl     1571    6-OMe        Et      C C-cycPr     1572    6-OMe        Et      C C-iPr     1573    6-OMe        Et      C C-nPr     1574    6-OMe        Et      C C-Et     1575    5-F, 6-OMe   cycPr   C C-cycPr     1576    5-F, 6-OMe   cycPr   C C-iPr     1577    5-F, 6-OMe   cycPr   C C-nPr     1578    5-F, 6-OMe   cycPr   C C-Et     1579    5-F, 6-OMe   cycPr   C C-3-Pyridyl     1580    5-F, 6-OMe   cycPr   C C-2-furanyl     1581    5-F, 6-OMe   cycPr   C C-3-furanyl     1582    5-F, 6-OMe   cycPr   C C-2-thienyl     1583    5-F, 6-OMe   cycPr   C C-3-thienyl     1584    5-F, 6-OMe   iPr     C C-cycPr     1585    5-F, 6-OMe   iPr     C C-iPr     1586    5-F, 6-OMe   iPr     C C-nPr     1587    5-F, 6-OMe   iPr     C C-Et     1588    5-F, 6-OMe   iPr     C C-3-Pyridyl     1589    5-F, 6-OMe   iPr     C C-2-furanyl     1590    5-F, 6-OMe   iPr     C C-3-furanyl     1591    5-F, 6-OMe   iPr     C C-2-thienyl     1592    5-F, 6-OMe   iPr     C C-3-thienyl     1593    5-F, 6-OMe   Et      C C-cycPr     1594    5-F, 6-OMe   Et      C C-iPr     1595    5-F, 6-OMe   Et      C C-nPr     1596    5-F, 6-OMe   Et      C C-Et     1597    6-NMe.sub.2  cycPr   C C-cycPr     1598    6-NMe.sub.2  cycPr   C C-iPr     1599    6-NMe.sub.2  cycPr   C C-nPr     1600    6-NMe.sub.2  cycPr   C C-Et     1601    6-NMe.sub.2  cycPr   C C-3-Pyridyl     1602    6-NMe.sub.2  cycPr   C C-2-furanyl     1603    6-NMe.sub.2  cycPr   C C-3-furanyl     1604    6-NMe.sub.2  cycPr   C C-2-thienyl     1605    6-NMe.sub.2  cycPr   C C-3-thienyl     1606    6-NMe.sub.2  iPr     C C-cycPr     1607    6-NMe.sub.2  iPr     C C-iPr     1608    6-NMe.sub.2  iPr     C C-nPr     1609    6-NMe.sub.2  iPr     C C-Et     1610    6-NMe.sub.2  iPr     C C-3-Pyridyl     1611    6-NMe.sub.2  iPr     C C-2-furanyl     1612    6-NMe.sub.2  iPr     C C-3-furanyl     1613    6-NMe.sub.2  iPr     C C-2-thienyl     1614    6-NMe.sub.2  iPr     C C-3-thienyl     1615    6-NMe.sub.2  Et      C C-cycPr     1616    6-NMe.sub.2  Et      C C-iPr     1617    6-NMe.sub.2  Et      C C-nPr     1618    6-NMe.sub.2  Et      C C-Et     1619    6-COCH.sub.3 cycPr   C C-cycPr     1620    6-COCH.sub.3 cycPr   C C-iPr     1621    6-COCH.sub.3 cycPr   C C-nPr     1622    6-COCH.sub.3 cycPr   C C-Et     1623    6-COCH.sub.3 cycPr   C C-3-Pyridyl     1624    6-COCH.sub.3 cycPr   C C-2-furanyl     1625    6-COCH.sub.3 cycPr   C C-3-furanyl     1626    6-COCH.sub.3 cycPr   C C-2-thienyl     1627    6-COCH.sub.3 cycPr   C C-3-thienyl     1628    6-COCH.sub.3 iPr     C C-cycPr     1629    6-COCH.sub.3 iPr     C C-iPr     1630    6-COCH.sub.3 iPr     C C-nPr     1631    6-COCH.sub.3 iPr     C C-Et     1632    6-COCH.sub.3 iPr     C C-3-Pyridyl     1633    6-COCH.sub.3 iPr     C C-2-furanyl     1634    6-COCH.sub.3 iPr     C C-3-furanyl     1635    6-COCH.sub.3 iPr     C C-2-thienyl     1636    6-COCH.sub.3 iPr     C C-3-thienyl     1637    6-COCH.sub.3 Et      C C-cycPr     1638    6-COCH.sub.3 Et      C C-iPr     1639    6-COCH.sub.3 Et      C C-nPr     1640    6-COCH.sub.3 Et      C C-Et     1641    6-CH.sub.3   cycPr   C C-cycPr     1642    6-CH.sub.3   cycPr   C C-nPr     1643    6-CH.sub.3   cycPr   C C-Et     1644    6-CH.sub.3   cycPr   C C-3-Pyridyl     1645    6-CH.sub.3   cycPr   C C-2-furanyl     1646    6-CH.sub.3   cycPr   C C-3-furanyl     1647    6-CH.sub.3   cycPr   C C-2-thienyl     1648    6-CH.sub.3   cycPr   C C-3-thienyl     1649    6-CH.sub.3   iPr     C C-nPr     1650    6-CH.sub.3   iPr     C C-Et     1651    6-CH.sub.3   iPr     C C-3-Pyridyl     1652    6-CH.sub.3   iPr     C C-2-furanyl     1653    6-CH.sub.3   iPr     C C-3-furanyl     1654    6-CH.sub.3   iPr     C C-2-thienyl     1655    6-CH.sub.3   iPr     C C-3-thienyl     1656    6-CH.sub.3   Et      C C-cycPr     1657    6-CH.sub.3   Et      C C-nPr     1658    6,8-diCl     cycPr   C C-cycPr     1659    6,8-diCl     cycPr   C C-iPr     1660    6,8-diCl     cycPr   C C-nPr     1661    6,8-diCl     cycPr   C C-Et     1662    6,8-diCl     cycPr   C C-3-Pyridyl     1663    6,8-diCl     cycPr   C C-2-furanyl     1664    618-diCl     cycPr   C C-3-furanyl     1665    6,8-diCl     cycPr   C C-2-thienyl     1666    6,8-diCl     cycPr   C C-3-thienyl     1667    6,8-diCl     iPr     C C-cycPr     1668    6,8-diCl     iPr     C C-iPr     1669    6,8-diCl     iPr     C C-nPr     1670    6,8-diCl     iPr     C C-Et     1671    6,8-diCl     iPr     C C-3-Pyridyl     1672    6,8-diCl     iPr     C C-2-furanyl     1673    6,8-diCl     iPr     C C-3-furanyl     1674    6,8-diCl     iPr     C C-2-thienyl     1675    6,8-diCl     iPr     C C-3-thienyl     1676    6,8-diCl     Et      C C-cycPr     1677    6,8-diCl     Et      C C-iPr     1678    6,8-diCl     Et      C C-nPr     1679    6,8-diCl     Et      C C-Et     1680    5,6,8-triF   cycPr   C C-cycPr     1681    5,6,8-triF   cycPr   C C-iPr     1682    5,6,8-triF   cycPr   C C-nPr     1683    5,6,8-triF   cycPr   C C-Et     1684    5,6,8-triF   cycPr   C C-3-Pyridyl     1685    5,6,8-triF   cycPr   C C-2-furanyl     1686    5,6,8-triF   cycPr   C C-3-furanyl     1687    5,6,8-triF   cycPr   C C-2-thienyl     1688    5,6,8-triF   cycPr   C C-3-thienyl     1689    5,6,8-triF   iPr     C C-cycPr     1690    5,6,8-triF   iPr     C C-iPr     1691    5,6,8-triF   iPr     C C-nPr     1692    5,6,8-triF   iPr     C C-Et     1693    5,6,8-triF   iPr     C C-3-Pyridyl     1694    5,6,8-triF   iPr     C C-2-furanyl     1695    5,6,8-triF   iPr     C C-3-furanyl     1696    5,6,8-triF   iPr     C C-2-thienyl     1697    5,6,8-triF   iPr     C C-3-thienyl     1698    5,6,8-triF   Et      C C-cycPr     1699    5,6,8-triF   Et      C C-iPr     1700    5,6,8-triF   Et      C C-nPr     1701    5,6,8-triF   Et      C C-Et     1702    5,8-diF      cycPr   C C-cycPr     1703    5,8-diF      cycPr   C C-iPr     1704    5,8-diF      cycPr   C C-nPr     1705    5,8-diF      cycPr   C C-Et     1706    5,8-diF      cycPr   C C-3-Pyridyl     1707    5,8-diF      cycPr   C C-2-furanyl     1708    5,8-diF      cycPr   C C-3-furanyl     1709    5,8-diF      cycPr   C C-2-thienyl     1710    5,8-diF      cycPr   C C-3-thienyl     1711    5,8-diF      iPr     C C-cycPr     1712    5,8-diF      iPr     C C-iPr     1713    5,8-diF      iPr     C C-nPr     1714    5,8-diF      iPr     C C-Et     1715    5,8-diF      iPr     C C-3-Pyridyl     1716    5,8-diF      iPr     C C-2-furanyl     1717    5,8-diF      iPr     C C-3-furanyl     1718    5,8-diF      iPr     C C-2-thienyl     1719    5,8-diF      iPr     C C-3-thienyl     1720    5,8-diF      Et      C C-cycPr     1721    5,8-diF      Et      C C-iPr     1722    5,8-diF      Et      C C-nPr     1723    5,8-diF      Et      C C-Et     1724    6-iPr        cycPr   C C-cycPr     1725    6-iPr        cycPr   C C-iPr     1726    6-iPr        cycPr   C C-nPr     1727    6-iPr        cycPr   C C-Et     1728    6-iPr        cycPr   C C-3-Pyridyl     1729    6-iPr        cycPr   C C-2-furanyl     1730    6-iPr        cycPr   C C-3-furanyl     1731    6-iPr        cycPr   C C-2-thienyl     1732    6-iPr        cycPr   C C-3-thienyl     1733    6-iPr        iPr     C C-cycPr     1734    6-iPr        iPr     C C-iPr     1735    6-iPr        iPr     C C-nPr     1736    6-iPr        iPr     C C-Et     1737    6-iPr        iPr     C C-3-Pyridyl     1738    6-iPr        iPr     C C-2-furanyl     1739    6-iPr        iPr     C C-3-furanyl     1740    6-iPr        iPr     C C-2-thienyl     1741    6-iPr        iPr     C C-3-thienyl     1742    6-iPr        Et      C C-cycPr     1743    6-iPr        Et      C C-iPr     1744    6-iPr        Et      C C-nPr     1745    6-iPr        Et      C C-Et     1746    6-OCF.sub.3  cycPr   C C-cycPr     1747    6-OCF.sub.3  cycPr   C C-iPr     1748    6-OCF.sub.3  cycPr   C C-nPr     1749    6-OCF.sub.3  cycPr   C C-Et     1750    6-OCF.sub.3  cycPr   C C-3-Pyridyl     1751    6-OCF.sub.3  cycPr   C C-2-furanyl     1752    6-OCF.sub.3  cycPr   C C-3-furanyl     1753    6-OCF.sub.3  cycPr   C C-2-thienyl     1754    6-OCF.sub.3  cycPr   C C-3-thienyl     1755    6-OCF.sub.3  iPr     C C-cycPr     1756    6-OCF.sub.3  iPr     C C-iPr     1757    6-OCF.sub.3  iPr     C C-nPr     1758    6-OCF.sub.3  iPr     C C-Et     1759    6-OCF.sub.3  iPr     C C-3-Pyridyl     1760    6-OCF.sub.3  iPr     C C-2-furanyl     1761    6-OCF.sub.3  iPr     C C-3-furanyl     1762    6-OCF.sub.3  iPr     C C-2-thienyl     1763    6-OCF.sub.3  iPr     C C-3-thienyl     1764    6-OCF.sub.3  Et      C C-cycPr     1765    6-OCF.sub.3  Et      C C-iPr     1766    6-OCF.sub.3  Et      C C-nPr     1767    6-OCF.sub.3  Et      C C-Et     1768    6-(pyrazol-5-yl)                          cycPr   C C-cycPr     1769    6-(pyrazol-5-yl)                          cycPr   C C-iPr     1770    6-(pyrazol-5-yl)                          cycPr   C C-nPr     1771    6-(pyrazol-5-yl)                          cycPr   C C-Et     1772    6-(pyrazol-5-yl)                          cycPr   C C-3-Pyridyl     1773    6-(pyrazol-5-yl)                          cycPr   C C-2-furanyl     1774    6-(pyrazol-5-yl)                          cycPr   C C-3-furanyl     1775    6-(pyrazol-5-yl)                          cycPr   C C-2-thienyl     1776    6-(pyrazol-5-yl)                          cycPr   C C-3-thienyl     1777    6-(pyrazol-5-yl)                          iPr     C C-cycPr     1778    6-(pyrazol-5-yl)                          iPr     C C-iPr     1779    6-(pyrazol-5-yl)                          iPr     C C-nPr     1780    6-(pyrazol-5-yl)                          iPr     C C-Et     1781    6-(pyrazol-5-yl)                          iPr     C C-3-Pyridyl     1782    6-(pyrazol-5-yl)                          iPr     C C-2-furanyl     1783    6-(pyrazol-5-yl)                          iPr     C C-3-furanyl     1784    6-(pyrazol-5-yl)                          iPr     C C-2-thienyl     1785    6-(pyrazol-5-yl)                          iPr     C C-3-thienyl     1786    6-(pyrazol-5-yl)                          Et      C C-cycPr     1787    6-(pyrazol-5-yl)                          Et      C C-iPr     1788    6-(pyrazol-5-yl)                          Et      C C-nPr     1789    6-(pyrazol-5-yl)                          Et      C C-Et     1790    H            cycPr   C C-cycPr     1791    H            cycPr   C C-iPr     1792    H            cycPr   C C-nPr     1793    H            cycPr   C C-Et     1794    H            cycPr   C C-3-Pyridyl     1795    H            cycPr   C C-2-furanyl     1796    H            cycPr   C C-3-furanyl     1797    H            cycPr   C C-2-thienyl     1798    H            cycPr   C C-3-thienyl     1799    H            iPr     C C-cycPr     1800    H            iPr     C C-iPr     1801    H            iPr     C C-nPr     1802    H            iPr     C C-Et     1803    H            iPr     C C-3-Pyridyl     1804    H            iPr     C C-2-furanyl     1805    H            iPr     C C-3-furanyl     1806    H            iPr     C C-2-thienyl     1807    H            iPr     C C-3-thienyl     1808    H            Et      C C-cycPr     1809    H            Et      C C-iPr     1810    H            Et      C C-nPr     1811    H            Et      C C-Et     1812    6-Ph         cycPr   C C-cycPr     1813    6-Ph         cycPr   C C-iPr     1814    6-Ph         cycPr   C C-nPr     1815    6-Ph         cycPr   C C-Et     1816    6-Ph         cycPr   C C-3-Pyridyl     1817    6-Ph         cycPr   C C-2-furanyl     1818    6-Ph         cycPr   C C-3-furanyl     1819    6-Ph         cycPr   C C-2-thienyl     1820    6-Ph         cycPr   C C-3-thienyl     1821    6-Ph         iPr     C C-cycPr     1822    6-Ph         iPr     C C-iPr     1823    6-Ph         iPr     C C-nPr     1824    6-Ph         iPr     C C-Et     1825    6-Ph         iPr     C C-3-Pyridyl     1826    6-Ph         iPr     C C-2-furanyl     1827    6-Ph         iPr     C C-3-furanyl     1828    6-Ph         iPr     C C-2-thienyl     1829    6-Ph         iPr     C C-3-thienyl     1830    6-Ph         Et      C C-cycPr     1831    6-Ph         Et      C C-iPr     1832    6-Ph         Et      C C-nPr     1833    6-Ph         Et      C C-Et     1834    6-CN         cycPr   C C-cycPr     1835    6-CN         cycPr   C C-iPr     1836    6-CN         cycPr   C C-nPr     1837    6-CN         cycPr   C C-Et     1838    6-CN         cycPr   C C-3-Pyridyl     1839    6-CN         cycPr   C C-2-furanyl     1840    6-CN         cycPr   C C-3-furanyl     1841    6-CN         cycPr   C C-2-thienyl     1842    6-CN         cycPr   C C-3-thienyl     1843    6-CN         iPr     C C-cycPr     1844    6-CN         iPr     C C-iPr     1845    6-CN         iPr     C C-nPr     1846    6-CN         iPr     C C-Et     1847    6-CN         iPr     C C-3-Pyridyl     1848    6-CN         iPr     C C-2-furanyl     1849    6-CN         iPr     C C-3-furanyl     1850    6-CN         iPr     C C-2-thienyl     1851    6-CN         iPr     C C-3-thienyl     1852    6-CN         Et      C C-cycPr     1853    6-CN         Et      C C-iPr     1854    6-CN         Et      C C-nPr     1855    6-CN         Et      C C-Et     1856    6-NO.sub.2   cycPr   C C-cycPr     1857    6-NO.sub.2   cycPr   C C-iPr     1858    6-NO.sub.2   cycPr   C C-nPr     1859    6-NO.sub.2   cycPr   C C-Et     1860    6-NO.sub.2   cycPr   C C-3-Pyridyl     1861    6-NO.sub.2   cycPr   C C-2-furanyl     1862    6-NO.sub.2   cycPr   C C-3-furanyl     1863    6-NO.sub.2   cycPr   C C-2-thienyl     1864    6-NO.sub.2   cycPr   C C-3-thienyl     1865    6-NO.sub.2   iPr     C C-cycPr     1866    6-NO.sub.2   iPr     C C-iPr     1867    6-NO.sub.2   iPr     C C-nPr     1868    6-NO.sub.2   iPr     C C-Et     1869    6-NO.sub.2   iPr     C C-3-Pyridyl     1870    6-NO.sub.2   iPr     C C-2-furanyl     1871    6-NO.sub.2   iPr     C C-3-furanyl     1872    6-NO.sub.2   iPr     C C-2-thienyl     1873    6-NO.sub.2   iPr     C C-3-thienyl     1874    6-NO.sub.2   Et      C C-cycPr     1875    6-NO.sub.2   Et      C C-iPr     1876    6-NO.sub.2   Et      C C-nPr     1877    6-NO.sub.2   Et      C C-Et     1878    6-NHMe       cycPr   C C-cycPr     1879    6-NHMe       cycPr   C C-iPr     1880    6-NHMe       cycPr   C C-nPr     1881    6-NHMe       cycPr   C C-Et     1882    6-NHMe       cycPr   C C-3-Pyridyl     1883    6-NHMe       cycPr   C C-2-furanyl     1884    6-NHMe       cycPr   C C-3-furanyl     1885    6-NHMe       cycPr   C C-2-thienyl     1886    6-NHMe       cycPr   C C-3-thienyl     1887    6-NHMe       iPr     C C-cycPr     1888    6-NHMe       iPr     C C-iPr     1889    6-NHNe       iPr     C C-nPr     1890    6-NHMe       iPr     C C-Et     1891    6-NHMe       iPr     C C-3-Pyridyl     1892    6-NHMe       iPr     C C-2-furanyl     1893    6-NHNe       iPr     C C-3-furanyl     1894    6-NHNe       iPr     C C-2-thienyl     1895    6-NHMe       iPr     C C-3-thienyl     1896    6-NHNe       Et      C C-cycPr     1897    6-NHNe       Et      C C-iPr     1898    6-NHMe       Et      C C-nPr     1899    6-NHMe       Et      C C-Et     1900    6,7-diCl     cycPr   C C-cycPr     1901    6,7-diCl     cycPr   C C-nPr     1902    6,7-diCl     cycPr   C C-Et     1903    6,7-diCl     cycPr   C C-3-Pyridyl     1904    6,7-diCl     cycPr   C C-2-furanyl     1905    6,7-diCl     cycPr   C C-3-furanyl     1906    6,7-diCl     cycPr   C C-2-thienyl     1907    6,7-diCl     cycPr   C C-3-thienyl     1908    6,7-diCl     iPr     C C-cycPr     1909    6,7-diCl     iPr     C C-nPr     1910    6,7-diCl     iPr     C C-Et     1911    6,7-diCl     iPr     C C-3-Pyridyl     1912    6,7-diCl     iPr     C C-2-furanyl     1913    6,7-diCl     iPr     C C-3-furanyl     1914    6,7-diCl     iPr     C C-2-thienyl     1915    6,7-diCl     iPr     C C-3-thienyl     1916    6,7-diCl     Et      C C-cycPr     1917    6,7-diCl     Et      C C-iPr     1918    6,7-diCl     Et      C C-nPr     1919    6,7-diCl     Et      C C-Et     1920    7-Cl         cycPr   C C-nPr     1921    7-Cl         cycPr   C C-Et     1922    7-Cl         cycPr   C C-3-Pyridyl     1923    7-Cl         cycPr   C C-2-furanyl     1924    7-Cl         cycPr   C C-3-furanyl     1925    7-Cl         cycPr   C C-2-thienyl     1926    7-Cl         cycPr   C C-3-thienyl     1927    7-Cl         iPr     C C-nPr     1928    7-Cl         iPr     C C-Et     1929    7-Cl         iPr     C C-3-Pyridyl     1930    7-Cl         iPr     C C-2-furanyl     1931    7-Cl         iPr     C C-3-furanyl     1932    7-Cl         iPr     C C-2-thienyl     1933    7-Cl         iPr     C C-3-thienyl     1934    7-Cl         Et      C C-cycPr     1935    7-Cl         Et      C C-iPr     1936    7-Cl         Et      C C-nPr     1937    7-Cl         Et      C C-Et     ______________________________________      Unless otherwise noted, stereochemistry is (+/-).

                  TABLE 4     ______________________________________      ##STR45##     Ex. #          W      X        Y    Z    R.sup.1                                         R.sup.2     ______________________________________     2001 CH     CCl      CH   N    CF.sub.3                                         C C-nPr     2002 CH     CCl      CH   N    CF.sub.3                                         C C-Bu     2003 CH     CCl      CH   N    CF.sub.3                                         C C-iBu     2004 CH     CCl      CH   N    CF.sub.3                                         C C-tBu     2005 CH     CCl      CH   N    CF.sub.3                                         C C-Et     2006 CH     CCl      CH   N    CF.sub.3                                         C C-Me     2007 CH     CCl      CH   N    CF.sub.3                                         C C-Ph     2008 CH     CCl      CH   N    CF.sub.3                                         C C-2-Pyridyl     2009 CH     CCl      CH   N    CF.sub.3                                         C C-3-Pyridyl     2010 CH     CCl      CH   N    CF.sub.3                                         C C-4-Pyridyl     2011 CH     CCl      CH   N    CF.sub.3                                         C C-2-furanyl     2012 CH     CCl      CH   N    CF.sub.3                                         C C-3-furanyl     2013 CH     CCl      CH   N    CF.sub.3                                         C C-2-thienyl     2014 CH     CCl      CH   N    CF.sub.3                                         C C-3-thienyl     2015 CH     CCl      CH   N    CF.sub.3                                         CHCH-cycPr     2016 CH     CCl      CH   N    CF.sub.3                                         CHCH-iPr     2017 CH     CCl      CH   N    CF.sub.3                                         CHCH-nPr     2018 CH     CCl      CH   N    CF.sub.3                                         CHCH-Bu     2019 CH     CCl      CH   N    CF.sub.3                                         CHCH-iBu     2020 CH     CCl      CH   N    CF.sub.3                                         CHCH-tBu     2021 CH     CCl      CH   N    CF.sub.3                                         CHCH-Et     2022 CH     CCl      CH   N    CF.sub.3                                         CHCH-Me     2023 CH     CCl      CH   N    CF.sub.3                                         CHCH-Ph     2024 CH     CCl      CH   N    CF.sub.3                                         CHCH-2-Pyridyl     2025 CH     CCl      CH   N    CF.sub.3                                         CHCH-3-Pyridyl     2026 CH     CCl      CH   N    CF.sub.3                                         CHCH-4-Pyridyl     2027 CH     CCl      CH   N    CF.sub.3                                         CHCH-2-furanyl     2028 CH     CCl      CH   N    CF.sub.3                                         CHCH-3-furanyl     2029 CH     CCl      CH   N    CF.sub.3                                         CHCH-2-thienyl     2030 CH     CCl      CH   N    CF.sub.3                                         CHCH-3-thienyl     2031 CH     CCl      CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                         CH.sub.3     2032 CH     CCl      CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2     2033 CH     CCl      CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     2034 CH     CCl      CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 CH.sub.3     2035 CH     CCl      CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 -cycPr     2036 CH     CCl      CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 -tBu     2037 CH     CCl      CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 -2-Pyridyl     2038 CH     CCl      CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 -3-Pyridyl     2039 CH     CCl      CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 -4-Pyridyl     2040 CH     CCl      CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 -2-furanyl     2041 CH     CCl      CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 -3-furanyl     2042 CH     CCl      CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 -2-thienyl     2043 CH     CCl      CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 -3-thienyl     2044 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         C C-cycPr     2045 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         C C-iPr     2046 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         C C-nPr     2047 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         C C-Bu     2048 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         C C-iBu     2049 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         C C-tBu     2050 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         C C-Et     2051 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         C C-Me     2052 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         C C-Ph     2053 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         C C-2-Pyridyl     2054 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         C C-3-Pyridyl     2055 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         C C-4-Pyridyl     2056 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         C C-2-furanyl     2057 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         C C-3-furanyl     2058 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         C C-2-thienyl     2059 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         C C-3-thienyl     2060 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CHCH-cycPr     2061 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CHCH-iPr     2062 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CHCH-nPr     2063 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CHCH-Bu     2064 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CHCH-iBu     2065 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CHCH-tBu     2066 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CHCH-Et     2067 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CHCH-Me     2068 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CHCH-Ph     2069 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CHCH-2-Pyridyl     2070 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CHCH-3-Pyridyl     2071 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CHCH-4-Pyridyl     2072 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CHCH-2-furanyl     2073 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CHCH-3-furanyl     2074 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CHCH-2-thienyl     2075 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CHCH-3-thienyl     2076 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                         CH.sub.3     2077 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2     2078 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     2079 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 CH.sub.3     2080 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 -cycPr     2081 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 -tBu     2082 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 -Ph     2083 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 -2-Pyridyl     2084 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 -3-Pyridyl     2085 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 -4-Pyridyl     2086 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 -2-furanyl     2087 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 -3-furanyl     2088 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 -2-thienyl     2089 CH     C(OCH.sub.3)                          CH   N    CF.sub.3                                         CH.sub.2 CH.sub.2 -3-thienyl     2090 CH     CH       CH   N    CF.sub.3                                         C C-cycPr     2091 CH     CH       CH   N    CF.sub.3                                         C C-iPr     2092 CH     CH       CH   N    CF.sub.3                                         C C-nPr     2093 CH     CH       CH   N    CF.sub.3                                         C C-Et     2094 CH     CH       CH   N    CF.sub.3                                         C C-3-Pyridyl     2095 CH     CH       CH   N    CF.sub.3                                         C C-2-furanyl     2096 CH     CH       CH   N    CF.sub.3                                         C C-3-furanyl     2097 CH     CH       CH   N    CF.sub.3                                         C C-2-thienyl     2098 CH     CH       CH   N    CF.sub.3                                         C C-3-thienyl     2099 CH     CCl      N    CH   CF.sub.3                                         C C-iPr     2100 CH     CCl      N    CH   CF.sub.3                                         C C-nPr     2101 CH     CCl      N    CH   CF.sub.3                                         C C-Bu     2102 CH     CCl      N    CH   CF.sub.3                                         C C-iBu     2103 CH     CCl      N    CH   CF.sub.3                                         C C-tBu     2104 CH     CCl      N    CH   CF.sub.3                                         C C-Et     2105 CH     CCl      N    CH   CF.sub.3                                         C C-Me     2106 CH     CCl      N    CH   CF.sub.3                                         C C-Ph     2107 CH     CCl      N    CH   CF.sub.3                                         C C-2-Pyridyl     2108 CH     CCl      N    CH   CF.sub.3                                         C C-3-Pyridyl     2109 CH     CCl      N    CH   CF.sub.3                                         C C-4-Pyridyl     2110 CH     CCl      N    CH   CF.sub.3                                         C C-2-furanyl     2111 CH     CCl      N    CH   CF.sub.3                                         C C-3-furanyl     2112 CH     CCl      N    CH   CF.sub.3                                         C C-2-thienyl     2113 CH     CCl      N    CH   CF.sub.3                                         C C-3-thienyl     2114 CH     CCl      N    CH   CF.sub.3                                         CHCH-cycPr     2115 CH     CCl      N    CH   CF.sub.3                                         CHCH-iPr     2116 CH     CCl      N    CH   CF.sub.3                                         CHCH-nPr     2117 CH     CCl      N    CH   CF.sub.3                                         CHCH-Bu     2118 CH     CCl      N    CH   CF.sub.3                                         CHCH-iBu     2119 CH     CCl      N    CH   CF.sub.3                                         CHCH-tBu     2120 CH     CCl      N    CH   CF.sub.3                                         CHCH-Et     2121 CH     CCl      N    CH   CF.sub.3                                         CHCH-Me     2122 CH     CCl      N    CH   CF.sub.3                                         CHCH-Ph     2123 CH     CCl      N    CH   CF.sub.3                                         CHCH-2-Pyridyl     2124 CH     CCl      N    CH   CF.sub.3                                         CHCH-3-Pyridyl     2125 CH     CCl      N    CH   CF.sub.3                                         CHCH-4-Pyridyl     2126 CH     CCl      N    CH   CF.sub.3                                         CHCH-2-furanyl     2127 CH     CCl      N    CH   CF.sub.3                                         CHCH-3-furanyl     2128 CH     CCl      N    CH   CF.sub.3                                         CHCH-2-thienyl     2129 CH     CCl      N    CH   CF.sub.3                                         CHCH-3-thienyl     2130 CH     CCl      N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                         CH.sub.3     2131 CH     CCl      N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2     2132 CH     CCl      N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     2133 CH     CCl      N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 CH.sub.3     2134 CH     CCl      N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -cycPr     2135 CH     CCl      N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -tBu     2136 CH     CCl      N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -Ph     2137 CH     CCl      N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -2-Pyridyl     2138 CH     CCl      N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -3-Pyridyl     2139 CH     CCl      N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -4-Pyridyl     2140 CH     CCl      N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -2-furanyl     2141 CH     CCl      N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -3-furanyl     2142 CH     CCl      N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -2-thienyl     2143 CH     CCl      N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -3-thienyl     2144 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         C C-iPr     2145 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         C C-nPr     2146 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         C C-Bu     2147 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         C C-iBu     2148 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         C C-tBu     2149 CH     C(CCH.sub.3)                          N    CH   CF.sub.3                                         C C-Et     2150 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         C C-Me     2151 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         C C-Ph     2152 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         C C-2-Pyridyl     2153 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         C C-3-Pyridyl     2154 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         C C-4-Pyridyl     2155 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         C C-2-furanyl     2156 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         C C-3-furanyl     2157 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         C C-2-thienyl     2158 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         C C-3-thienyl     2159 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CHCH-cycPr     2160 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CHCH-iPr     2161 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CHCH-nPr     2162 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CHCH-Bu     2163 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CHCH-iBu     2164 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CHCH-tBu     2165 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CHCH-Et     2166 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CHCH-Me     2167 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CHCH-Ph     2168 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CHCH-2-Pyridyl     2169 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CHCH-3-Pyridyl     2170 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CHCH-4-Pyridyl     2171 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CHCH-2-furanyl     2172 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CHCH-3-furanyl     2173 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CHCH-2-thienyl     2174 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CHCH-3-thienyl     2175 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                         CH.sub.3     2176 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2     2177 CH     C(CCH.sub.3)                          N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     2178 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 CH.sub.3     2179 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -cycPr     2180 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -tBu     2181 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -Ph     2182 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -2-Pyridyl     2183 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -3-Pyridyl     2184 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -4-Pyridyl     2185 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -2-furanyl     2186 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -3-furanyl     2187 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -2-thienyl     2188 CH     C(OCH.sub.3)                          N    CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -3-thienyl     2189 CH     CH       N    CH   CF.sub.3                                         C C-cycPr     2190 CH     CH       N    CH   CF.sub.3                                         C C-iPr     2191 CH     CH       N    CH   CF.sub.3                                         C C-nPr     2192 CH     CH       N    CH   CF.sub.3                                         C C-Et     2193 CH     CH       N    CH   CF.sub.3                                         C C-3-Pyridyi     2194 CH     CH       N    CH   CF.sub.3                                         C C-2-furanyl     2195 CH     CH       N    CH   CF.sub.3                                         C C-3-furanyl     2196 CH     CH       N    CH   CF.sub.3                                         C C-2-thienyl     2197 CH     CH       N    CH   CF.sub.3                                         C C-3-thienyi     2198 CCl    N        CH   CH   CF.sub.3                                         C C-cycPr     2199 CCl    N        CH   CH   CF.sub.3                                         C C-iPr     2200 CCl    N        CH   CH   CF.sub.3                                         C C-nPr     2201 CCl    N        CH   CH   CF.sub.3                                         C C-Bu     2202 CCl    N        CH   CH   CF.sub.3                                         C C-iBu     2203 CCl    N        CH   CH   CF.sub.3                                         C C-tBu     2204 CCl    N        CH   CH   CF.sub.3                                         C C-Et     2205 CCl    N        CH   CH   CF.sub.3                                         C C-Me     2206 CCl    N        CH   CH   CF.sub.3                                         C C-Ph     2207 CCl    N        CH   CH   CF.sub.3                                         C C-2-Pyridyl     2208 CCl    N        CH   CH   CF.sub.3                                         C C-3-Pyridyl     2209 CCl    N        CH   CH   CF.sub.3                                         C C-4-Pyridyl     2210 CCl    N        CH   CH   CF.sub.3                                         C C-2-furanyl     2211 CCl    N        CH   CH   CF.sub.3                                         C C-3-furanyl     2212 CCl    N        CH   CH   CF.sub.3                                         C C-2-thienyl     2213 CCl    N        CH   CH   CF.sub.3                                         C C-3-thienyl     2214 CCl    N        CH   CH   CF.sub.3                                         CHCH-cycPr     2215 CCl    N        CH   CH   CF.sub.3                                         CHCH-iPr     2216 CCl    N        CH   CH   CF.sub.3                                         CHCH-nPr     2217 CCl    N        CH   CH   CF.sub.3                                         CHCH-Bu     2218 CCl    N        CH   CH   CF.sub.3                                         CHCH-iBu     2219 CCl    N        CH   CH   CF.sub.3                                         CHCH-tBu     2220 CCl    N        CH   CH   CF.sub.3                                         CHCH-Et     2221 CCl    N        CH   CH   CF.sub.3                                         CHCH-Me     2222 CCl    N        CH   CH   CF.sub.3                                         CHCH-Ph     2223 CCl    N        CH   CH   CF.sub.3                                         CHCH-2-Pyridyl     2224 CCl    N        CH   CH   CF.sub.3                                         CHCH-3-Pyridyl     2225 CCl    N        CH   CH   CF.sub.3                                         CHCH-4-Pyridyl     2226 CCl    N        CH   CH   CF.sub.3                                         CHCH-2-furanyl     2227 CCl    N        CH   CH   CF.sub.3                                         CHCH-3-furanyl     2228 CCl    N        CH   CH   CF.sub.3                                         CHCH-2-thienyl     2229 CCl    N        CH   CH   CF.sub.3                                         CHCH-3-thienyl     2230 CCl    N        CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                         CH.sub.3     2231 CCl    N        CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2     2232 CCl    N        CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     2233 CCl    N        CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 CH.sub.3     2234 CCl    N        CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -cycPr     2235 CCl    N        CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -tBu     2236 CCl    N        CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -Ph     2237 CCl    N        CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -2-Pyridyl     2238 CCl    N        CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -3-Pyridyl     2239 CCl    N        CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -4-Pyridyl     2240 CCl    N        CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -2-furanyl     2241 CCl    N        CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -3-furanyl     2242 CCl    N        CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -2-thienyl     2243 CCl    N        CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -3-thienyl     2244 CH     N        CH   CH   CF.sub.3                                         C C-iPr     2245 CH     N        CH   CH   CF.sub.3                                         C C-nPr     2246 CH     N        CH   CH   CF.sub.3                                         C C-Et     2247 CH     N        CH   CH   CF.sub.3                                         C C-3-Pyridyl     2248 CH     N        CH   CH   CF.sub.3                                         C C-2-furanyl     2249 CH     N        CH   CH   CF.sub.3                                         C C-3-furanyl     2250 CH     N        CH   CH   CF.sub.3                                         C C-2-thienyl     2251 CH     N        CH   CH   CF.sub.3                                         C C-3-thienyl     2252 N      CCl      CH   CH   CF.sub.3                                         C C-cycPr     2253 N      CCl      CH   CH   CF.sub.3                                         C C-iPr     2254 N      CCl      CH   CH   CF.sub.3                                         C C-nPr     2255 N      CCl      CH   CH   CF.sub.3                                         C C-Bu     2256 N      CCl      CH   CH   CF.sub.3                                         C C-iBu     2257 N      CCl      CH   CH   CF.sub.3                                         C C-tBu     2258 N      CCl      CH   CH   CF.sub.3                                         C C-Et     2259 N      CCl      CH   CH   CF.sub.3                                         C C-Me     2260 N      CCl      CH   CH   CF.sub.3                                         C C-Ph     2261 N      CCl      CH   CH   CF.sub.3                                         C C-2-Pyridyl     2262 N      CCl      CH   CH   CF.sub.3                                         C C-3-Pyridyl     2263 N      CCl      CH   CH   CF.sub.3                                         C C-4-Pyridyl     2264 N      CCl      CH   CH   CF.sub.3                                         C C-2-furanyl     2265 N      CCl      CH   CH   CF.sub.3                                         C C-3-furanyl     2266 N      CCl      CH   CH   CF.sub.3                                         C C-2-thienyl     2267 N      CCl      CH   CH   CF.sub.3                                         C C-3-thienyl     2268 N      CCl      CH   CH   CF.sub.3                                         CHCH-cycPr     2269 N      CCl      CH   CH   CF.sub.3                                         CHCH-iPr     2270 N      CCl      CH   CH   CF.sub.3                                         CHCH-nPr     2271 N      CCl      CH   CH   CF.sub.3                                         CHCH-Bu     2272 N      CCl      CH   CH   CF.sub.3                                         CHCH-iBu     2273 N      CCl      CH   CH   CF.sub.3                                         CHCH-tBu     2274 N      CCl      CH   CH   CF.sub.3                                         CHCH-Et     2275 N      CCl      CH   CH   CF.sub.3                                         CHCH-Me     2276 N      CCl      CH   CH   CF.sub.3                                         CHCH-Ph     2277 N      CCl      CH   CH   CF.sub.3                                         CHCH-2-Pyridyl     2278 N      CCl      CH   CH   CF.sub.3                                         CHCH-3-Pyridyl     2279 N      CCl      CH   CH   CF.sub.3                                         CHCH-4-Pyridyl     2280 N      CCl      CH   CH   CF.sub.3                                         CHCH-2-furanyl     2281 N      CCl      CH   CH   CF.sub.3                                         CHCH-3-furanyl     2282 N      CCl      CH   CH   CF.sub.3                                         CHCH-2-thienyl     2283 N      CCl      CH   CH   CF.sub.3                                         CHCH-3-thienyl     2284 N      CCl      CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                         CH.sub.3     2285 N      CCl      CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2     2286 N      CCl      CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     2287 N      CCl      CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 CH.sub.3     2288 N      CCl      CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -cycPr     2289 N      CCl      CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -tBu     2290 N      CCl      CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -Ph     2291 N      CCl      CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -2-Pyridyl     2292 N      CCl      CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -3-Pyridyl     2293 N      CCl      CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -4-Pyridyl     2294 N      CCl      CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -2-furanyl     2295 N      CCl      CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -3-furanyl     2296 N      CCl      CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -2-thienyl     2297 N      CCl      CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -3-thienyl     2298 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         C C-cycPr     2299 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         C C-iPr     2300 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         C C-nPr     2301 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         C C-Bu     2302 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         C C-iBu     2303 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         C C-tBu     2304 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         C C-Et     2305 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         C C-Me     2306 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         C C-Ph     2307 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         C C-2-Pyridyl     2308 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         C C-3-Pyridyl     2309 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         C C-4-Pyridyl     2310 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         C C-2-furanyl     2311 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         C C-3-furanyl     2312 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         C C-2-thienyl     2313 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         C C-3-thienyl     2314 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CHCH-cycPr     2315 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CHCH-iPr     2316 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CHCH-nPr     2317 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CHCH-Bu     2318 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CHCH-iBu     2319 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CHCH-tBu     2320 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CHCH-Et     2321 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CHCH-Me     2322 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CHCH-Ph     2323 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CHCH-2-Pyridyl     2324 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CHCH-3-Pyridyl     2325 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CHCH-4-Pyridyl     2326 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CHCH-2-furanyl     2327 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CHCH-3-furanyl     2328 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CHCH-2-thienyl     2329 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CHCH-3-thienyl     2330 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                         CH.sub.3     2331 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2     2332 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3     2333 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 CH.sub.3     2334 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -cycPr     2335 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -tBu     2336 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -Ph     2337 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -2-Pyridyl     2338 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -3-Pyridyl     2339 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -4-Pyridyl     2340 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -2-furanyl     2341 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -3-furanyl     2342 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -2-thienyl     2343 N      C(OCH.sub.3)                          CH   CH   CF.sub.3                                         CH.sub.2 CH.sub.2 -3-thienyl     2344 N      CH       CH   CH   CF.sub.3                                         C C-cycPr     2345 N      CH       CH   CH   CF.sub.3                                         C C-iPr     2346 N      CH       CH   CH   CF.sub.3                                         C C-nPr     2347 N      CH       CH   CH   CF.sub.3                                         C C-Et     2348 N      CH       CH   CH   CF.sub.3                                         C C-3-Pyridyl     2349 N      CH       CH   CH   CF.sub.3                                         C C-2-furanyl     2350 N      CH       CH   CH   CF.sub.3                                         C C-3-furanyl     2351 N      CH       CH   CH   CF.sub.3                                         C C-2-thienyl     2352 N      CH       CH   CH   CF.sub.3                                         C C-3-thienyl     ______________________________________      *Unless otherwise noted, stereochemistry is (+/-).

                                      TABLE 5     __________________________________________________________________________      ##STR46##     Ex. #         G  R.sup.1  R.sup.2    m.p. (°C.)                                      Mass Spec     __________________________________________________________________________     2401         6-Cl            cycPr    C C-Et       137-138.5     2402         6-Cl            CF.sub.3 C C-Et     178     2403         6-Cl            Et       C C-Et     175-176     2404         6-Cl            CH.sub.3 CH.sub.3   202   212.0440     2405         6-Cl            CH.sub.3 C C-cycPr  184     2406         6-Cl            CH.sub.3 CH.sub.3   221-222                                      228.0262     2407         6-Cl            CH.sub.3 C C-iPr    168   264.0790     2408         6-Cl            CF.sub.3 CHCH-cycPr(cis)     2409         6-Cl            CF.sub.3 C C-iPr    167-168     2410         6-Cl            CF.sub.3 CHCH-iPr(cis)                                146-147     2411         6-Cl            CF.sub.3 CH.sub.2 CH.sub.2 -iPr                                129-131     2412         6-Cl            CF.sub.3 C C-iPr    116-118     2413         6-Cl            CF.sub.3 CHCH-iPr(trans)                                127-129     2414         6-Cl            OMe      CH.sub.2 CH.sub.2 -Ph                                      318.0897     2415         6-Cl            OEt      Ph               304                                      (MH.sup.+)     2416         6-Cl            CF.sub.3 C C-1-d-cycPr                                180-181                                      317.0406     2417         6-Cl            CF.sub.3 C C-1-d-cycPr                                133-134                                      317.0417     2418         6-Cl            CF.sub.3 C C-1-Me-cycPr                                158-159                                      347.0785     2419         6-Cl            CF.sub.3 Butyl      135-136     2420         6-Cl            CF.sub.3 C C-cycBu  183-185                                      330.0495     2421         6-Cl            CF.sub.3 C(Me).sub.2 CC CCH     2422         6-Cl            CF.sub.3 CF.sub.3   148-149     2423         6-Cl            CF.sub.3 C C --CF.sub.3                                155-156     2424         6-Cl            CF.sub.3 Pentyl     2425         6-Cl            CF.sub.3 C C-Ph           352.0353     2426         6-Cl            CF.sub.3 C C-3-py     2427         6-Cl            CF.sub.3 C C-2-thiazole     2428         6-Cl            CF.sub.3 NH-iBu     182-183     2429         6-Cl            CF.sub.3 C C-4-py     2430         6-Cl            CH.sub.3 C C-Ph     181-182                                      298.0620     2431         6-Cl            iPr      C C-iPr    oil   292.1106     2432         6-Cl            iPr      C C-iBu    oil   306.1268     2433         6-Cl            iPr      C C-cycPr  amorphous                                      290.0938     2434         6-Cl            iPr      C C-Ph     177-178                                      326.0955     2435         6-Cl            Et       C C-cycPr  183-184                                      276.0792     2436         6-Cl            Et       C C-iPr    143-144                                      278.0958     2437         6-Cl            Et       C C-Ph     165-166                                      312.0790     2438         6-Cl            Et       C C-iBu    136-137                                      292.1100     2439         6-Cl            cycPr    C C-cycPr  142-143                                      288.0789     2440         6-Cl            cycPr    C C-iPr    152-153                                      290.0950     2441         6-Cl            cycPr    C C-Ph     156-157                                      324.0778     2442         6-Cl            cycPr    C C-iBu    142-143                                      304.1102     2443         6-Cl            iPr      CH.sub.2 CH.sub.2 -iPr                                oil   296.1417     2444         6-Cl            cycPr    CH.sub.2 CH.sub.2 CHCH.sub.2                                oil   278.0946     2445         6-Cl            C C-cycPr                     C C-cycPr  129-131                                      312.0786     2446         6-Cl            CF.sub.3 C C-iBu    176-177                                      332.0664     2447         6-Cl            CC-iPr   C C-iPr    139   316.1104     2448         6-Cl            iPr      CH.sub.2 CH.sub.2 CHCH.sub.2                                oil   280.1109     2449         6-Cl            C CH     C C-iPr    161-162                                      274.0638     2450         6-Cl            CF.sub.3 C(Me)2CHCH.sub.2                                113-114                                      320.0662     2451         6-Cl            CF.sub.3 C C-2-Py     2452         6-Cl            CF.sub.3 C C-nPr    193-194                                      318.0500                                      (MH.sup.+)     2453         6-Cl            CF.sub.3 C C-1-OH-cycPr     2454         6-Cl            C CH     C C-Et     157-159                                      260.0483     2455         6-Cl            CF.sub.3 CH.sub.2 -iPr                                177-178                                      308.0659     2456         6-Cl            iPr      CH.sub.2 -iPr                                132-133                                      282.1261     2457         6-Cl            cycPr    CH.sub.2 -iPr                                136-137                                      280.1104     2458         6-Cl            iPr      C C-Et     amorphous     2459         6-Cl            CF.sub.3 C C-Et     142-146     2460         6-Cl            CF.sub.3 C C-Et     143-147     2461         6-Cl            CF.sub.3 CH.sub.2 CH.sub.2 -iPr                                amorphous     2462         6-Cl            CF.sub.3 CH.sub.2 CH.sub.2 -iPr                                amorphous     2463         6-Cl            iPr      C C-cycPr  amorphous     2464         6-Cl            iPr      C C-cycPr  amorphous     2465         6-Cl            CF.sub.3 CH.sub.2 --C C-Me                                196-199     2466         6-Cl            CF.sub.3 CH.sub.2 --C C-Et                                140-145     2467         6-Cl            CF.sub.3 NHCH.sub.2 CH.sub.2 CH.sub.3                                184-185                                      309.0628     2468         6-Cl            CF.sub.3 C C-2-furanyl                                170-171     2469         6-Cl            CF.sub.3 C C-3-thienyl                                176.7-178     2470         6-Cl            CF.sub.3 C C-3-furanyl                                155-156     2471         6-Cl            CF.sub.3 OBu        132-133     2472         6-Cl            CF.sub.3 C C-5-thiazolyl                                  196-196.5     2473         6-Cl            CF.sub.3 CHCH-3-Py (t)                                188-189     2474         6-Cl            CF.sub.3 C C-3-py     183.5     2475         6-Cl            CF.sub.3 C C-3-py     2476         6-Cl            CF.sub.3 CHCH-iPr(t)     2477         6-Cl            CF.sub.3 CHCH-iPr(t)     2478         6-Cl            CF.sub.3 OCH.sub.2 CH.sub.2 -iPr                                      338.0766     2479         6-Cl            CF.sub.3 OCH.sub.2 CH.sub.2 --OMe                                127-128                                      326.0391     2480         6-Cl            CF.sub.3 CHCH-cycPr(t)                                136-137     2481         6-Cl            CF.sub.3 CHCH-cycPr(t)                                amorphous     2482         6-Cl            CF.sub.3 CHCH-cycPr(t)                                amorphous     2483         6-Cl            CF.sub.3 CHCH-nPr(t)                                127-128     2484         6-Cl            CF.sub.3 CHCH-Et(t) 146-147     2485         6-Cl            CF.sub.3 C C-Me     243-244     2486         6-Cl            CF.sub.3 C C-iPr    116-118     2487         6-F            iPr      C C-iPr          276.1400     2488         6-F            iPr      C C-cycPr        274.1243     2489         6-F            CF.sub.3 C C-iPr          302.0797     2490         6-F            CF.sub.3 CH.sub.2 CH.sub.2 -iPr                                      306.1111     2491         6-F            CF.sub.3 C C-cycPr        300.0638     2492         6-F            CF.sub.3 C C-Ph           336.0648     2493         6-F            CF.sub.3 Pentyl           306.1106     2494         6-F            CF.sub.3 C C-iPr     2495         6-F            CF.sub.3 C C-iPr          302.0792     2496         6-F            CF.sub.3 C C-Et           288.0650                                      (MH.sup.+)     2497         6-F            CF.sub.3 C C-nPr          302.0796     2498         6-F            CF.sub.3 Butyl            292.0947     __________________________________________________________________________      *Unless otherwise noted, stereochemistry is (+/-).

Utility

The compounds of this invention possess reverse transcriptase inhibitory activity, in particular, HIV inhibitory efficacy. The compounds of formula (I) possess HIV reverse transcriptase inhibitory activity and are therefore useful as antiviral agents for the treatment of HIV infection and associated diseases. The compounds of formula (I) possess HIV reverse transcriptase inhibitory activity and are effective as inhibitors of HIV growth. The ability of the compounds of the present invention to inhibit viral growth or infectivity is demonstrated in standard assay of viral growth or infectivity, for example, using the assay described below.

The compounds of formula (I) of the present invention are also useful for the inhibition of HIV in an ex vivo sample containing HIV or expected to be exposed to HIV. Thus, the compounds of the present invention may be used to inhibit HIV present in a body fluid sample (for example, a serum or semen sample) which contains or is suspected to contain or be exposed to HIV.

The compounds provided by this invention are also useful as standard or reference compounds for use in tests or assays for determining the ability of an agent to inhibit viral clone replication and/or HIV reverse transcriptase, for example in a pharmaceutical research program. Thus, the compounds of the present invention may be used as a control or reference compound in such assays and as a quality control standard. The compounds of the present invention may be provided in a commercial kit or container for use as such standard or reference compound.

Since the compounds of the present invention exhibit specificity for HIV reverse transcriptase, the compounds of the present invention may also be useful as diagnostic reagents in diagnostic assays for the detection of HIV reverse transcriptase. Thus, inhibition of the reverse transcriptase activity in an assay (such as the assays described herein) by a compound of the present invention would be indicative of the presence of HIV reverse transcriptase and HIV virus.

As used herein "μg" denotes microgram, "mg" denotes milligram, "g" denotes gram, "μL" denotes microliter, "mL" denotes milliliter, "L" denotes liter, "nM" denotes nanomolar, "μM" denotes micromolar, "mM" denotes millimolar, "M" denotes molar and "nm" denotes nanometer. "Sigma" stands for the Sigma-Aldrich Corp. of St. Louis, Mo.

HIV RNA Assay

DNA Plasmids and in vitro RNA transcripts

Plasmid pDAB 72 containing both gag and pol sequences of BH10 (bp 113-1816) cloned into PTZ 19R was prepared according to Erickson-Viitanen et al. AIDS Research and Human Retroviruses 1989, 5, 577. The plasmid was linearized with Bam HI prior to the generation of in vitro RNA transcripts using the Riboprobe Gemini system II kit (Promega) with T7 RNA polymerase. Synthesized RNA was purified by treatment with RNase free DNAse (Promega), phenol-chloroform extraction, and ethanol precipitation. RNA transcripts were dissolved in water, and stored at -70° C. The concentration of RNA was determined from the A₂₆₀.

Probes

Biotinylated capture probes were purified by HPLC after synthesis on an Applied Biosystems (Foster City, Calif.) DNA synthesizer by addition of biotin to the 5' terminal end of the oligonucleotide, using the biotin-phosphoramidite reagent of Cocuzza, Tet. Lett. 1989, 30, 6287. The gag biotinylated capture probe (5-biotin-CTAGCTCCCTGCTTGCCCATACTA 3') was complementary to nucleotides 889-912 of HXB2 and the pol biotinylated capture probe (5'-biotin -CCCTATCATTTTTGGTTTCCAT 3') was complementary to nucleotides 2374-2395 of HXB2. Alkaline phosphatase conjugated oligonucleotides used as reporter probes were prepared by Syngene (San Diego, Calif.). The pol reporter probe (5'CTGTCTTACTTTGATAAAACCTC 3') was complementary to nucleotides 2403-2425 of HXB2. The gag reporter probe (5'CCCAGTATTTGTCTACAGCCTTCT 3') was complementary to nucleotides 950-973 of HXB2. All nucleotide positions are those of the GenBank Genetic Sequence Data Bank as accessed through the Genetics Computer Group Sequence Analysis Software Package (Devereau Nucleic Acids Research 1984, 12, 387). The reporter probes were prepared as 0.5 μM stocks in 2×SSC (0.3M NaCl, 0.03M sodium citrate), 0.05M Tris pH 8.8, 1 mg/mL BSA. The biotinylated capture probes were prepared as 100 μM stocks in water.

Streptavidin coated plates

Streptavidin coated plates were obtained from Du Pont Biotechnology Systems (Boston, Mass.).

Cells and virus stocks

MT-2 and MT-4 cells were maintained in RPMI 1640 supplemented with 5% fetal calf serum (FCS) for MT-2 cells or 10% FCS for MT-4 cells, 2 mM L-glutamine and 50 μg/mL gentamycin, all from Gibco. HIV-1 RF was propagated in MT-4 cells in the same medium. Virus stocks were prepared approximately 10 days after acute infection of MT-4 cells and stored as aliquots at -70° C. Infectious titers of HIV-1(RF) stocks were 1-3×10⁷ PFU (plaque forming units)/mL as measured by plaque assay on MT-2 cells (see below). Each aliquot of virus stock used for infection was thawed only once.

For evaluation of antiviral efficacy, cells to be infected were subcultured one day prior to infection. On the day of infection, cells were resuspended at 5×10⁵ cells/mL in RPMI 1640, 5% FCS for bulk infections or at 2×10⁶ /mL in Dulbecco's modified Eagles medium with 5% FCS for infection in microtiter plates. Virus was added and culture continued for 3 days at 37° C.

HIV RNA assay

Cell lysates or purified RNA in 3M or 5M GED were mixed with 5M GED and capture probe to a final guanidinium isothiocyanate concentration of 3M and a final biotin oligonucleotide concentration of 30 nM. Hybridization was carried out in sealed U bottom 96 well tissue culture plates (Nunc or Costar) for 16-20 hours at 37° C. RNA hybridization reactions were diluted three-fold with deionized water to a final guanidinium isothiocyanate concentration of 1M and aliquots (150 μL) were transferred to streptavidin coated microtiter plates wells. Binding of capture probe and capture probe-RNA hybrid to the immobilized streptavidin was allowed to proceed for 2 hours at room temperature, after which the plates were washed 6 times with DuPont ELISA plate wash buffer (phosphate buffered saline(PBS), 0.05% Tween 20.) A second hybridization of reporter probe to the immobilized complex of capture probe and hybridized target RNA was carried out in the washed streptavidin coated well by addition of 120 μl of a hybridization cocktail containing 4×SSC, 0.66% Triton×100, 6.66% deionized formamide, 1 mg/mL BSA and 5 nM reporter probe. After hybridization for one hour at 37° C., the plate was again washed 6 times. Immobilized alkaline phosphatase activity was detected by addition of 100 μL of 0.2 mM 4-methylumbelliferyl phosphate (MUBP, JBL Scientific) in buffer δ(2.5M diethanolamine pH 8.9 (JBL Scientific), 10 mM MgCl₂, 5 mM zinc acetate dihydrate and 5 mM N-hydroxyethyl-ethylene-diamine-triacetic acid). The plates were incubated at 37° C. Fluorescence at 450 nM was measured using a microplate fluorometer (Dynateck) exciting at 365 nM.

Microplate based compound evaluation in HIV-1 infected MT-2 cells

Compounds to be evaluated were dissolved in DMSO and diluted in culture medium to twice the highest concentration to be tested and a maximum DMSO concentration of 2%. Further three-fold serial dilutions of the compound in culture medium were performed directly in U bottom microtiter plates (Nunc). After compound dilution, MT-2 cells (50 μL) were added to a final concentration of 5×10⁵ per mL (1×10⁵ per well). Cells were incubated with compounds for 30 minutes at 37° C. in a CO₂ incubator. For evaluation of antiviral potency, an appropriate dilution of HIV-1 (RF) virus stock (50 μL) was added to culture wells containing cells and dilutions of the test compounds. The final volume in each well was 200 μL. Eight wells per plate were left uninfected with 50 μL of medium added in place of virus, while eight wells were infected in the absence of any antiviral compound. For evaluation of compound toxicity, parallel plates were cultured without virus infection.

After 3 days of culture at 37° C. in a humidified chamber inside a CO₂ incubator, all but 25 μL of medium/well was removed from the HIV infected plates. Thirty seven μL of 5M GED containing biotinylated capture probe was added to the settled cells and remaining medium in each well to a final concentration of 3M GED and 30 nM capture probe. Hybridization of the capture probe to HIV RNA in the cell lysate was carried out in the same microplate well used for virus culture by sealing the plate with a plate sealer (Costar), and incubating for 16-20 hrs in a 37° C. incubator. Distilled water was then added to each well to dilute the hybridization reaction three-fold and 150 μL of this diluted mixture was transferred to a streptavidin coated microtiter plate. HIV RNA was quantitated as described above. A standard curve, prepared by adding known amounts of pDAB 72 in vitro RNA transcript to wells containing lysed uninfected cells, was run on each microtiter plate in order to determine the amount of viral RNA made during the infection.

In order to standardize the virus inoculum used in the evaluation of compounds for antiviral activity, dilutions of virus were selected which resulted in an IC₉₀ value (concentration of compound required to reduce the HIV RNA level by 90%) for dideoxycytidine (ddC) of 0.2 μg/mL. IC₉₀ values of other antiviral compounds, both more and less potent than ddC, were reproducible using several stocks of HIV-1 (RF) when this procedure was followed. This concentration of virus corresponded to ˜3×10⁵ PFU (measured by plaque assay on MT-2 cells) per assay well and typically produced approximately 75% of the maximum viral RNA level achievable at any virus inoculum. For the HIV RNA assay, IC₉₀ values were determined from the percent reduction of net signal (signal from infected cell samples minus signal from uninfected cell samples) in the RNA assay relative to the net signal from infected, untreated cells on the same culture plate (average of eight wells). Valid performance of individual infection and RNA assay tests was judged according to three criteria. It was required that the virus infection should result in an RNA assay signal equal to or greater than the signal generated from 2 ng of pDAB 72 in vitro RNA transcript. The IC₉₀ for ddC, determined in each assay run, should be between 0.1 and 0.3 μg/mL. Finally, the plateau level of viral RNA produced by an effective reverse transcriptase inhibitor should be less than 10% of the level achieved in an uninhibited infection. A compound was considered active if its IC₉₀ was found to be less than 20 μM.

For antiviral potency tests, all manipulations in microtiter plates, following the initial addition of 2×concentrated compound solution to a single row of wells, were performed using a Perkin Elmer/Cetus ProPette.

HIV-1 RT Assay Materials and Methods

This assay measures HIV-1 RT RNA dependent DNA polymerase activity by the incorporation of 3H dTMP onto the template primer Poly (rA) oligo (dT)12-18. The template primer containing the incorporated radioactivity was separated from unincorporated label by one of two methods:

Method 1. The template primer was precipitated with TCA, collected on glass fiber filters and counted for radioactivity with a scintillation counter.

Method 2. The currently used method is more rapid and convenient. The template primer is captured on an diethyl amino ethyl (DEAE) ion exchange membrane which is then counted for radioactivity after washing off the free nucleotide.

Materials and Reagents

The template primer Poly (rA) oligo (dT)12-18 and dTTP were purchased from Pharmacia Biotech. The template primer and nucleotide were dissolved in diethyl pyrocarbonate water to a concentration of 1 mg/ml and 5.8 mM respectively. The substrates were aliquoted (template primer at 20 μl/aliquot, dTTP at 9 μl/aliquot) and frozen at -20 C.

The 3H dTTP (2.5 mCi/ml in 10 mM Tricine at pH 7.6; specific activity of 90-120 Ci/mmol) and the recombinant HIV-1 Reverse Transcriptase (HxB2 background; 100 U/10 μl in 100 mM potassium phosphate at pH 7.1, 1 mM dithiothreitol and 50% glycerol) were purchased from DuPont NEN. 1 Unit of enzyme is defined by DuPont NEN as the amount required to incorporate 1 nmol of labelled dTTP into acid-insoluble material in 10 minutes at 37 C. The 3H dTTP was aliquoted at 23.2 μl/microfuge tube (58 μCi) and frozen at -20 C. The HIV-1 Reverse Transcriptase (RT) was diluted 10 fold with RT buffer (80 mM KCl, 50 mM Tris HCl, 12 mM MgCl2, 1 mM DTT, 50 μM EGTA, 5 mg/ml BSA, 0.01% Triton-X 100, pH 8.2) and aliquoted at 10 μl/microfuge tube (10 Units/10 μl). One aliquot (enough for 8 assays) was diluted further to 10 Units/100 μl and aliquoted into 8 tubes (1.25 Units/12.5 μl). All aliquots were frozen at -70 C.

The Millipore Multiscreen DE 96 well filter plates, multiscreen plate adaptors, and microplate press-on adhesive sealing film were purchased from Millipore. The filter plate containing 0.65 μm pore size diethyl amino ethyl cellulose (DEAE) paper disks was pretreated with 0.3M ammonium formate and 10 mM sodium pyrophosphate (2 times 200 μl /well) at pH 8.0 prior to use. A Skatron 96 well cell harvester and glass fiber filter mats were purchased from Skatron Instruments. Microscint 20 scintillation cocktail was purchased from Packard. Beckman Ready Flow III scintillation cocktail was purchased from Beckman.

HIV-1 RT Assay

The enzyme and substrate mixture were freshly prepared from the above stock solutions. 1.25 Units of enzyme was diluted with RT buffer (containing 5 mg/ml BSA) to a concentration of 0.05 Units/10 μl or 0.7 nM. Final enzyme and BSA concentrations in the assay were 0.01 Units or 0.14 nM and 1 mg/ml respectively. The inhibitor and substrate mixture were diluted with RT buffer containing no BSA. All inhibitors were dissolved in dimethyl sulfoxide (DMSO) at a stock concentration of 3 mM and stored at -20 C. after use. A Biomek robot was used to dilute the inhibitors in a 96 well plate. Inhibitors were initially diluted 96 fold from stock and then serially diluted two times (10 fold/dilution) from 31.25 μM to 3125 nM and 312.5 nM. Depending on the potency of the inhibitor, one of the three dilutions was further diluted. Typically the highest concentration (31.25 μM) was serially diluted three times at 5 fold/dilution to 6.25, 1.25, and 0.25 μM. Final inhibitor concentrations in the assay were 12.5, 2.5, 0.5, and 0.1 μM. For potent inhibitors of HIV-1 RT, the final inhibitor concentrations used were 0.1 or 0.01 that stated above. The substrate mixture contained 6.25 μg/ml of Poly (rA) oligo (dT)12-18 and 12.5 μM of dTTP (58 μCi 3H dTTP). The final substrate concentrations were 2.5 μg/ml and 5 μM respectively.

Using the Beckman Instruments Biomek robot, 10 μl of HIV-1 RT was combined with 20 μl of inhibitor in a 96 well U bottom plate. The enzyme and inhibitor were preincubated at ambient temperature for 6 minutes. 20 μl of the substrate mixture was added to each well to initiate the reaction (total volume was 50 μl). The reactions were incubated at 37 C. and terminated after 45 minutes.

For method 1, 200 μl of an ice-cold solution of 13% tritrichloroacetic acid (TCA) and 10 mM sodium pyrophosphate was added to each of the 96 wells. The 96 well plate was then placed in an ice-water bath for 30 minutes. Using A Skatron 96 well cell harvester, the acid precipitable material was collected on a glass fiber filter mat that had been presoaked in 13% TCA and 10 mM sodium pyrophosphate. The filter disks were washed 3 times (2.0 ml/wash) with 1N HCl and 10 mM sodium pyrophosphate. The filter disks were punched out into scintillation vials, 2.0 ml of Beckman Ready Flow III scintillant was added, and the vials were counted for radioactivity for 1 minute.

For method 2, the assay was terminated with the addition of 175 μl/well of 50 mM EDTA at pH 8.0. Then 180 μl of the mixture was transferred to a pretreated Millipore DE 96 well filter plate. Vacuum was applied to the filter plate to aspirate away the liquid and immobilize the template primer on the DEAE filter disks. Each well was washed 3 times with 200 μl of 0.3M ammonium formate and 10 mM sodium pyrophosphate at pH 8.0. 50 μl of microscint 20 scintillation cocktail was added to each well and the plate was counted for radioactivity on a Packard Topcount at 1 minute/well.

The IC₅₀ values are calculated with the equation:

    IC.sub.50 = Inh!/(1/fractional activity -1)

where the fractional activity=RT activity (dpms) in the presence of inhibitor/RT activity (dpms) in the absence of inhibitor. For a given inhibitor, the IC₅₀ values were calculated for the inhibitor concentrations that range between 0.1-0.8 fractional activity. The IC₅₀ values in this range (generally 2 values) were averaged. A compound was considered active if its IC₅₀ was found to be less than 12 μM.

Protein Binding and Mutant Resistance

In order to characterize NNRTI analogs for their clinical efficacy potential the effect of plasma proteins on antiviral potency and measurements of antiviral potency against wild type and mutant variants of HIV which carry amino acid changes in the known binding site for NNRTIs were examined. The rationale for this testing strategy is two fold:

1. Many drugs are extensively bound to plasma proteins. Although the binding affinity for most drugs for the major components of human plasma, namely, human serum albumin (HSA) or alpha-1-acid glycoprotein (AAG), is low, these major components are present in high concentration in the blood. Only free or unbound drug is available to cross the infected cell membrane for interaction with the target site (i.e., HIV-1 reverse transcriptase, HIV-1 RT). Therefore, the effect of added HSA+AAG on the antiviral potency in tissue culture more closely reflects the potency of a given compound in the clinical setting. The concentration of compound required for 90% inhibition of virus replication as measured in a sensitive viral RNA-based detection method is designated the IC90. The fold increase in apparent IC90 for test compounds in the presence or added levels of HSA and AAG that reflect in vivo concentrations (45 mg/ml HSA, 1 mg/ml AAG) was then calculated. The lower the fold increase, the more compound will be available to interact with the target site.

2. The combination of the high rate of virus replication in the infected individual and the poor fidelity of the viral RT results in the production of a quasi-species or mixtures of HIV species in the infected individual. These species will include a majority wild type species, but also mutant variants of HIV and the proportion of a given mutant will reflect its relative fitness and replication rate. Because mutant variants including mutants with changes in the amino acid sequence of the viral RT likely pre-exist in the infected individual's quasi-species, the overall potency observed in the clinical setting will reflect the ability of a drug to inhibit not only wild type HIV-1, but mutant variants as well. We thus have constructed, in a known genetic background, mutant variants of HIV-1 which carry amino acid substitutions at positions thought to be involved in NNRTI binding, and measured the ability of test compounds to inhibit replication of these mutant viruses. The concentration of compound required for 90% inhibition of virus replication as measured in a sensitive viral RNA-based detection method is designated the IC90. It is desirable to have a compound which has high activity against a variety of mutants.

Dosage and Formulation

The antiviral compounds of this invention can be administered as treatment for viral infections by any means that produces contact of the active agent with the agent's site of action, i.e., the viral reverse transcriptase, in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but preferably are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired. A daily dosage of active ingredient can be expected to be about 0.001 to about 1000 milligrams per kilogram of body weight, with the preferred dose being about 0.1 to about 30 mg/kg.

Dosage forms of compositions suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts, and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, supra, a standard reference text in this field.

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg magnesium stearic.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil can be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules should then be washed and dried.

Tablets

A large number of tablets can be prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

Suspension

An aqueous suspension can be prepared for oral administration so that each 5 mL contain 25 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mg of vanillin.

Injectable

A parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is sterilized by commonly used techniques.

Combination of components (a) and (b)

Each therapeutic agent component of this invention can independently be in any dosage form, such as those described above, and can also be administered in various ways, as described above. In the following description component (b) is to be understood to represent one or more agents as described previously. Thus, if components (a) and (b) are to be treated the same or independently, each agent of component (b) may also be treated the same or independently.

Components (a) and (b) of the present invention may be formulated together, in a single dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc.) as a combination product. When component (a) and (b) are not formulated together in a single dosage unit, the component (a) may be administered at the same time as component (b) or in any order; for example component (a) of this invention may be administered first, followed by administration of component (b), or they may be administered in the reverse order. If component (b) contains more that one agent, e.g., one RT inhibitor and one protease inhibitor, these agents may be administered together or in any order. When not administered at the same time, preferably the administration of component (a) and (b) occurs less than about one hour apart. Preferably, the route of administration of component (a) and (b) is oral. The terms oral agent, oral inhibitor, oral compound, or the like, as used herein, denote compounds which may be orally administered. Although it is preferable that component (a) and component (b) both be administered by the same route (that is, for example, both orally) or dosage form, if desired, they may each be administered by different routes (that is, for example, one component of the combination product may be administered orally, and another component may be administered intravenously) or dosage forms.

As is appreciated by a medical practitioner skilled in the art, the dosage of the combination therapy of the invention may vary depending upon various factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, and the effect desired, as described above.

The proper dosage of components (a) and (b) of the present invention will be readily ascertainable by a medical practitioner skilled in the art, based upon the present disclosure. By way of general guidance, typically a daily dosage may be about 100 milligrams to about 1.5 grams of each component. If component (b) represents more than one compound, then typically a daily dosage may be about 100 milligrams to about 1.5 grams of each agent of component (b). By way of general guidance, when the compounds of component (a) and component (b) are administered in combination, the dosage amount of each component may be reduced by about 70-80% relative to the usual dosage of the component when it is administered alone as a single agent for the treatment of HIV infection, in view of the synergistic effect of the combination.

The combination products of this invention may be formulated such that, although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized. In order to minimize contact, for example, where the product is orally administered, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. Another embodiment of this invention where oral administration is desired provides for a combination product wherein one of the active ingredients is coated with a sustained-release material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component. In each formulation wherein contact is prevented between components (a) and (b) via a coating or some other material, contact may also be prevented between the individual agents of component (b).

Dosage forms of the combination products of the present invention wherein one active ingredient is enteric coated can be in the form of tablets such that the enteric coated component and the other active ingredient are blended together and then compressed into a tablet or such that the enteric coated component is compressed into one tablet layer and the other active ingredient is compressed into an additional layer. Optionally, in order to further separate the two layers, one or more placebo layers may be present such that the placebo layer is between the layers of active ingredients. In addition, dosage forms of the present invention can be in the form of capsules wherein one active ingredient is compressed into a tablet or in the form of a plurality of microtablets, particles, granules or non-perils, which are then enteric coated. These enteric coated microtablets, particles, granules or non-perils are then placed into a capsule or compressed into a capsule along with a granulation of the other active ingredient.

These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time or concurrently by the same manner, will be readily apparent to those skilled in the art, based on the present disclosure.

Pharmaceutical kits useful for the treatment of HIV infection, which comprise a therapeutically effective amount of a pharmaceutical composition comprising a compound of component (a) and one or more compounds of component (b), in one or more sterile containers, are also within the ambit of the present invention. Sterilization of the container may be carried out using conventional sterilization methodology well known to those skilled in the art. Component (a) and component (b) may be in the same sterile container or in separate sterile containers. The sterile containers of materials may comprise separate containers, or one or more multi-part containers, as desired. Component (a) and component (b), may be separate, or physically combined into a single dosage form or unit as described above. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as for example, one or more pharmaceutically acceptable carriers, additional vials for mixing the components, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit.

Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein. 

What is claimed as new and desired to be secured by Letter Patent of United States is:
 1. A compound of formula (I): ##STR47## or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:A is O or S; W is N or CR³ ; X is N or CR⁴ ; Y is N or CR⁵ ; Z is N or CR⁶ ; provided that if two of W, X, Y, and Z are N, then the remaining are other than N; also, provided that if X is CR⁴ and R⁴ is F, Cl, Br, or I, then:(a) at least one of W, Y, and Z is other than CH; (b) R² is --OCHR⁷ R⁸ or --NHCHR⁷ R⁸ ; (c) if R² is --C.tbd.C--R⁸, then R⁸ is C₃₋₇ cycloalkyl substituted with 1 R⁹ ; or (d) any combination of (a), (b), and (c); R¹ is selected from CF₃, CF₂ H, C₂ F₅, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; R² is selected from --QCHR⁷ R⁸, --QCHR⁷ C.tbd.C--R⁸, --QCHR⁷ C═C--R⁸, --Q(CH₂)_(p) CHR⁷ R⁸, --C.tbd.C--R₈, --CH═CR⁷ R⁸, --(CH₂)_(p) CHR⁷ R⁸, --CHR⁷ C.tbd.C--R⁸, --CHR⁷ CH═CHR⁸, and CH═CHCHR⁷ R₈ ; provided that when R¹ is C₁₋₄ alkyl, then R² is --C.tbd.C--R⁸ ; provided that when R² is --(CH₂)_(p) CHR⁷ R⁸ and R⁸ is H or C₁₋₆ alkyl, then R¹ is other than cycloalkyl: R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7a), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ; alternatively, R³ and R⁴ together form --OCH₂ O--; R⁵ is selected from H, F, Cl, Br, and I; alternatively, R⁴ and R⁵ together form --OCH₂ O--or a fused benzo ring; R⁶ is selected from H, OH, C₁₋₃ alkoxy, --CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH₂ ; R⁷ is selected from H and C₁₋₃ alkyl; R^(7a) is selected from H and C₁₋₃ alkyl; R^(7b) is C₁₋₃ alkyl; R⁸ is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₆ alkenyl, C₃₋₇ cycloalkyl substituted with 0-2 R⁹, phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ; R⁹ is selected from ² H, OH, C₁₋₃ alkoxy, C₁₋₃ alkyl, and F; R¹⁰ is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ; R¹¹ is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷ R^(7a), CHO, C(O)CH₃, C(O)NH₂ ; Q is selected from O, S and NH; and, p is selected from 0, 1, and
 2. 2. A compound according to claim 1, wherein:R¹ is selected from CF₃, CF₂ H, C₂ F₅, C₁₋₃ alkyl, C₃₋₅ cycloalkyl; and, R⁸ is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₆ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰.
 3. A compound according to claim 2, wherein:R¹ is selected from CF₃, CF₂ H, C₂ F₅, C₂ H₅, isopropyl, and cyclopropyl; R³ is selected from H, F, Cl, Br, I, OCH₃, and CH₃ ; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7a), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; alternatively, R³ and R⁴ together form --OCH₂ O--; R⁵ is selected from H and F; R⁶ is selected from H, OH, OCH₃, --CN, F, CF₃, CH₃, and C(O)NH₂ ; R⁷ is selected from H and CH₃ ; R^(7a) is selected from H and CH₃ ; R^(7b) is CH₃ ; R⁸ is selected from H, C₁₋₄ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₄ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰ ; R⁹ is selected from ² H, OH, OCH₃, CH₃, and F; R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ; and, p is selected from 1 and
 2. 4. A compound according to claim 3, wherein:A is O; and, R¹ is selected from CF₃, CF₂ H, C₂ F₅ ; R² is selected from --OCHR⁷ R⁸, --OCH₂ C.tbd.C--R⁸, --OCH₂ C═C--R⁸, --OCH₂ CHR⁷ R⁸, --C.tbd.C--R⁸, --CH═CR⁷ R⁸, --CH₂ CHR⁷ R⁸, --CH₂ C.tbd.C--R⁸, CHR⁷ CH═CHR⁸, and CH═CHCHR⁷ R⁸ ; R³ is selected from H, F, Cl, Br, I; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C.tbd.CH, OCH₃, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), C(O)OR⁷, NR⁷ SO₂ R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; alternatively, R³ and R⁴ together form --OCH₂ O--; and, R¹¹ is selected from OH, OCH₃, CN, F, Cl, NR⁷ R^(7a), C(O)CH₃, and C(O)NH₂.
 5. A compound according to claim 4, wherein the compound is selected from:(±)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (-)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Cyclopropylethynyl-4-isopropyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Isopropylethynyl-4-trifluoromethyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Acetyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-(3-methyl)-1-buten-1-yl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Isopropylethynyl-4-trifluoromethyl-5,6-difluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Cyclopropylethynyl-6-chloro-4-trifluoromethyl-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(2-methoxyethoxy)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-propylamino-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(1-Butynyl)-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(1'-Hydroxy)-cyclopropylethynyl-4-trifluoromethyl-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(cyclopropylethynyl)-8-methoxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(cyclopropylethynyl)-7-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(1-butynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(isopentyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one: (±)-5,6-Difluoro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-(1-propynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-pentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-isopentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-butyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(2-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(2-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(1-propynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(2-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-butyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(phenylethyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Dimethylamino-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Dimethylamino-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Dimethylamino-4-pentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Dimethylamino-4-isopentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Acetyl-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6,8-Dichloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6,8-Dichloro-4-(phenylethyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6,8-Trifluoro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6,8-Trifluoro-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6,8-Trifluoro-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6,8-Trifluoro-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,8-Difluoro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,8-Difluoro-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,8-Difluoro-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,8-Difluoro-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-(phenylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-pentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-(isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-(phenylethyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluoromethoxy-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluoromethoxy-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluoromethoxy-4-(phenylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluoromethoxy-4-pentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluoromethoxy-4-(isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluoromethoxy-4-(phenylethyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(Phenylethyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(Isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(Phenylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(Pentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(Isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(4-methylpentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(cyclopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(isopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(isopropylethynyl)-4-cyclopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(isopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(isopropylethynyl)-4-ethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(1-butynyl)-4-ethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6,7-Dichloro-4-(isopropylethynyl)-4-cyclopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6,7-Dichloro-4-(isopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-7-Chloro-4-(cyclopropylethynyl)-4-cyclopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-7-Chloro-4-(isopropylethynyl)-4-cyclopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-7-Chloro-4-(4-methylpentynyl)-4-cyclopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-7-Chloro-4-(cyclopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-7-Chloro-4-(isopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-8-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(isopropylethynyl)-4-(trifluoromethyl)-8-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(-phenylethyl)-4-(trifluoromethyl)-8-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(cyclopropylethynyl)-4-(trifluoromethyl)-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one; and, (±)-4-(Cyclopropylethynyl)-4-(trifluoromethyl)-6-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one.
 6. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I): ##STR48## or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:A is O or S; W is N or CR³ ; X is N or CR⁴ ; Y is N or CR⁵ ; Z is N or CR⁶ ; provided that if two of W, X, Y, and Z are N, then the remaining are other than N; also, provided that if X is CR⁴ and R⁴ is F, Cl, Br, or I, then:(a) at least one of W, Y, and Z is other than CH; (b) R² is --OCHR⁷ R₈ or --NHCHR⁷ R⁸ ; (c) if R² is --C.tbd.C--R⁸, then R⁸ is C₃₋₇ cycloalkyl substituted with 1 R⁹ ; or (d) any combination of (a), (b), and (c); R¹ is selected from CF₃, CF₂ H, C₂ F₅, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; R² is selected from --QCHR⁷ R⁸, --QCHR⁷ C.tbd.C--R⁸, --QCHR⁷ C═C--R⁸, --Q(CH₂)_(p) CHR⁷ R⁸, --C.tbd.C--R⁸, --CH═CR⁷ R⁸, --(CH₂)_(p) CHR⁷ R⁸, --CHR⁷ C.tbd.C--R⁸, --CHR⁷ CH═CHR⁸, and CH═CHCHR⁷ R⁸ ; provided that when R¹ is C₁₋₄ alkyl, then R² is --C.tbd.C--R⁸ ; provided that when R² is --(CH₂)_(p) CHR⁷ R⁸ and R⁸ is H or C₁₋₆ alkyl, then R¹ is other than cycloalkyl; R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7a), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ; alternatively, R³ and R⁴ together form --OCH₂ O--; R⁵ is selected from H, F, Cl, Br, and I; alternatively, R⁴ and R⁵ together form --OCH₂ O-- or a fused benzo ring; R⁶ is selected from H, OH, C₁₋₃ alkoxy, --CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH₂ ; R⁷ is selected from H and C₁₋₃ alkyl; R^(7a) is selected from H and C₁₋₃ alkyl; R^(7b) is C₁₋₃ alkyl; R⁸ is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₆ alkenyl, C₃₋₇ cycloalkyl substituted with 0-2 R⁹, phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ; R⁹ is selected from ² H, OH, C₁₋₃ alkoxy, C₁₋₃ alkyl, and F; R¹⁰ is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ; R¹¹ is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷ R^(7a), CHO, C(O)CH₃, and C(O)NH₂ ; Q is selected from O, S and NH; and, p is selected from 0, 1, and
 2. 7. A pharmaceutical composition according to claim 6, wherein:R¹ is selected from CF₃, CF₂ H, C₂ F₅, C₁₋₃ alkyl, and C₃₋₅ cycloalkyl; and, R⁸ is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₆ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰.
 8. A pharmaceutical composition according to claim 7, wherein:R¹ is selected from CF₃, CF₂ H, C₂ F₅, C₂ H₅, isopropyl, and cyclopropyl; R³ is selected from H, F, Cl, Br, I, OCH₃, and CH₃ ; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C (O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7a), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; alternatively, R³ and R⁴ together form --OCH₂ O--; R⁵ is selected from H and F; R⁶ is selected from H, OH, OCH₃, --CN, F, CF₃, CH₃, and C(O)NH₂ ; R⁷ is selected from H and CH₃ ; R^(7a) is selected from H and CH₃ ; R^(7b) is CH₃ ; R⁸ is selected from H, C₁₋₄ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₄ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰ ; R⁹ is selected from ² H, OH, OCH₃, CH₃, and F; R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ; and, p is selected from 1 and
 2. 9. A pharmaceutical composition according to claim 8, wherein:A is O; R¹ is selected from CF₃, CF₂ H, and C₂ F₅ ; R² is selected from --OCHR⁷ R⁸, --OCH₂ C.tbd.C--R⁸, --OCH₂ C═C--R⁸, --OCH₂ CHR⁷ R⁸, --C.tbd.C--R⁸, --CH═CR⁷ R⁸, --CH₂ CHR⁷ R⁸, --CH₂ C.tbd.C--R⁸, CHR⁷ CH═CHR⁸, and CH═CHCHR⁷ R⁸ ; R³ is selected from H, F, Cl, Br, and I; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C.tbd.CH, OCH₃, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), C(O)OR⁷, NR⁷ SO₂ R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; alternatively, R³ and R⁴ together form --OCH₂ O--; and, R¹¹ is selected from OH, OCH₃, CN, F, Cl, NR⁷ R^(7a), C(O)CH₃, and C(O)NH₂.
 10. A pharmaceutical composition according to claim 6, wherein the compound is selected from:(±)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (-)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Cyclopropylethynyl-4-isopropyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Isopropylethynyl-4-trifluoromethyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Acetyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-(3-methyl)-1-buten-1-yl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Isopropylethynyl-4-trifluoromethyl-5,6-difluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Cyclopropylethynyl-6-chloro-4-trifluoromethyl-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(2-methoxyethoxy)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-propylamino-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(1-Butynyl)-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(1'-Hydroxy)-cyclopropylethynyl-4-trifluoromethyl-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(2-furanylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(2-pyridylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(cyclopropylethynyl)-8-methoxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(cyclopropylethynyl)-7-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(1-butynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(isopentyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-(1-propynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-pentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-isopentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-butyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(1-butynyl)-4-(trifluoromethyl)yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(2-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(2-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(1-propynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(2-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-butyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(phenylethyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Dimethylamino-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Dimethylamino-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Dimethylamino-4-pentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Dimethylamino-4-isopentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Acetyl-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6,8-Dichloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6,8-Dichloro-4-(phenylethyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6,8-Trifluoro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6,8-Trifluoro-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6,8-Trifluoro-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6,8-Trifluoro-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,8-Difluoro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,8-Difluoro-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,8-Difluoro-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,8-Difluoro-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-(phenylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-pentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-(isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-(phenylethyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluoromethoxy-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluoromethoxy-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluoromethoxy-4-(phenylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluoromethoxy-4-pentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluoromethoxy-4-(isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluoromethoxy-4-(phenylethyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(Phenylethyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(Isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(Phenylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(Pentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(Isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(4-methylpentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(cyclopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(isopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(isopropylethynyl)-4-cyclopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(isopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(isopropylethynyl)-4-ethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(1-butynyl)-4-ethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6,7-Dichloro-4-(isopropylethynyl)-4-cyclopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6,7-Dichloro-4-(isopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-7-Chloro-4-(cyclopropylethynyl)-4-cyclopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-7-Chloro-4-(isopropylethynyl)-4-cyclopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-7-Chloro-4-(4-methylpentynyl)-4-cyclopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-7-Chloro-4-(cyclopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-7-Chloro-4-(isopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-8-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(isopropylethynyl)-4-(trifluoromethyl)-8-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(phenylethyl)-4-(trifluoromethyl)-8-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(cyclopropylethynyl)-4-(trifluoromethyl)-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one; and, (±)-4-(Cyclopropylethynyl)-4-(trifluoromethyl)-6-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one.
 11. A method for treating HIV infection, comprising: administering to a host in need of such treatment a therapeutically effective amount of a compound of formula (I): ##STR49## or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:A is O or S; W is N or CR³ ; X is N or CR⁴ ; Y is N or CR⁵ ; Z is N or CR⁶ ; provided that if two of W, X, Y, and Z are N, then the remaining are other than N; also, provided that if X is CR⁴ and R⁴ is F, Cl, Br , or I, then:(a) at least one of W, Y, and Z is other than CH; (b) R₂ is --OCHR⁷ R⁸ or --NHCHR⁷ R⁸ ; (c) if R² is --C.tbd.C--R⁸, then R⁸ is C₃₋₇ cycloalkyl substituted with 1 R⁹ ; or (d) any combination of (a), (b), and (c); R¹ is selected from CF₃, CF₂ H, C₂ F₅, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; R² is selected from --QCHR⁷ R⁸, --QCHR⁷ C.tbd.C--R⁸, --QCHR⁷ C═C--R⁸, --Q(CH₂)_(p) CHR⁷ R⁸, --C.tbd.C--R⁸, --CH═CR⁷ R⁸, --(CH₂)_(p) CHR⁷ R⁸, --CHR⁷ C.tbd.C--R⁸, --CHR⁷ CH═CHR⁸, and CH═CHCHR⁷ R⁸ ; R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7a), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ; alternatively, R³ and R⁴ together form --OCH₂ O--; R⁵ is selected from H, F, Cl, Br, and I; alternatively, R⁴ and R⁵ together form --OCH₂ O-- or a fused benzo ring; R⁶ is selected from H, OH, C₁₋₃ alkoxy, --CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH₂ ; R⁷ is selected from H and C₁₋₃ alkyl; R^(7a) is selected from H and C₁₋₃ alkyl; R^(7b) is C₁₋₃ alkyl; R⁸ is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₆ alkenyl, C₃₋₇ cycloalkyl substituted with 0-2 R⁹, phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ; R⁹ is selected from ² H, OH, C₁₋₃ alkoxy, C₁₋₃ alkyl, and F; R¹⁰ is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ; R¹¹ is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷ R^(7a), CHO, C(O)CH₃, and C(O)NH₂ ; Q is selected from O, S and NH; and, p is selected from 0, 1, and
 2. 12. A method according to claim 11, wherein:R¹ is selected from CF₃, CF₂ H, C₂ F₅, C₁₋₃ alkyl, and C₃₋₅ cycloalkyl; and, R⁸ is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₆ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰.
 13. A method according to claim 12 wherein:R¹ is selected from CF₃, CF₂ H, C₂ F₅, C₂ H₅, isopropyl, and cyclopropyl; R³ is selected from H, F, Cl, Br, I, OCH₃, and CH₃ ; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7a), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; alternatively, R³ and R⁴ together form --OCH₂ O--; R⁵ is selected from H and F; R⁶ is selected from H, OH, OCH₃, --CN, F, CF₃, CH₃, and C(O)NH₂ ; R⁷ is selected from H and CH₃ ; R^(7a) is selected from H and CH₃ ; R^(7b) is CH₃ ; R⁸ is selected from H, C₁₋₄ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₄ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰ ; R⁹ is selected from ² H, OH, OCH₃, CH₃, and F; R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O) CH₃ ; and, p is selected from 1 and
 2. 14. A method according to claim 13, wherein:A is O; R¹ is selected from CF₃, CF₂ H, and C₂ F₅ ; R² is selected from --OCHR⁷ R⁸, --OCH₂ C.tbd.C--R⁸, --OCH₂ C═C--R⁸, --OCH₂ CHR⁷ R⁸, --C.tbd.C--R⁸, --CH═CR⁷ R⁸, --CH₂ CHR⁷ R⁸, --CH₂ C.tbd.C--R⁸, CHR⁷ CH═CHR⁸, and CH═CHCHR⁷ R⁸ ; R³ is selected from H, F, Cl, Br, and I; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C.tbd.CH, OCH₃, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), C(O)OR⁷, NR⁷ SO₂ R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; alternatively, R³ and R⁴ together form --OCH₂ O--; and, R¹¹ is selected from OH, OCH₃, CN, F, Cl, NR⁷ R^(7a), C(O)CH₃, and C(O)NH₂.
 15. A method according to claim 11, wherein the compound is selected from:(±)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (-)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Cyclopropylethynyl-4-isopropyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Isopropylethynyl-4-trifluoromethyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Acetyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-(3-methyl)-1-buten-1-yl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Isopropylethynyl-4-trifluoromethyl-5,6-difluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Cyclopropylethynyl-6-chloro-4-trifluoromethyl-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(2-methoxyethoxy)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-propylamino-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(1-Butynyl)-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(1'-Hydroxy)-cyclopropylethynyl-4-trifluoromethyl-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(2-furanylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(2-pyridylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(cyclopropylethynyl)-8-methoxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(cyclopropylethynyl)-7-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(1-butynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(isopentyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-(1-propynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-pentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-isopentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-butyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(2-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(2-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(1-propynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(2-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-butyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(phenylethyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Dimethylamino-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Dimethylamino-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Dimethylamino-4-pentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Dimethylamino-4-isopentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Acetyl-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6,8-Dichloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6,8-Dichloro-4-(phenylethyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6,8-Trifluoro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6,8-Trifluoro-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6,8-Trifluoro-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6,8-Trifluoro-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,8-Difluoro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,8-Difluoro-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,8-Difluoro-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,8-Difluoro-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-(phenylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-pentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-(isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-(phenylethyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluoromethoxy-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluoromethoxy-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluoromethoxy-4-(phenylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluoromethoxy-4-pentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluoromethoxy-4-(isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluoromethoxy-4-(phenylethyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(Phenylethyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(Isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(Phenylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(Pentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(Isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(4-methylpentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(cyclopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(isopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(isopropylethynyl)-4-cyclopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(isopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(isopropylethynyl)-4-ethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(1-butynyl)-4-ethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6,7-Dichloro-4-(isopropylethynyl)-4-cyclopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6,7-Dichloro-4-(isopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-7-Chloro-4-(cyclopropylethynyl)-4-cyclopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-7-Chloro-4-(isopropylethynyl)-4-cyclopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-7-Chloro-4-(4-methylpentynyl)-4-cyclopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-7-Chloro-4-(cyclopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-7-Chloro-4-(isopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-8-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(isopropylethynyl)-4-(trifluoromethyl)-8-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(phenylethyl)-4-(trifluoromethyl)-8-aza-1,4-dihydro-2H -3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(cyclopropylethynyl)-4-(trifluoromethyl)-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one; and, (±)-4-(Cyclopropylethynyl)-4-(trifluoromethyl)-6-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one.
 16. A method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of:(a) a compound of formula (I): ##STR50## or a stereoisomer or pharmaceutically acceptable salt form thereof; and, (b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors, wherein:A is O or S; W is N or CR³ ; X is N or CR⁴ ; Y is N or CR⁵ ; Z is N or CR⁶ ; provided that if two of W, X, Y, and Z are N, then the remaining are other than N; also, provided that if X is CR⁴ and R⁴ is F, Cl, Br, or I, then:(a) at least one of W, Y, and Z is other than CH; (b) R² is --OCHR⁷ R⁸ or --NHCHR⁷ R⁸ ; (c) if R² is --C.tbd.C--R⁸, then R⁸ is C₃₋₇ cycloalkyl substituted with 1 R⁹ ; or (d) any combination of (a), (b), and (c); R¹ is selected from CF₃, CF₂ H, C₂ F₅, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; R² is selected from --QCHR⁷ R⁸, --QCHR⁷ C.tbd.C--R⁸, --QCHR⁷ C═C--R⁸, --Q(CH₂)_(p) CHR⁷ R⁸, --C.tbd.C--R⁸, --CH═CR⁷ R⁸, --(CH₂)_(p) CHR⁷ R⁸, --CHR⁷ C.tbd.C--R⁸, --CHR⁷ CH═CHR⁸, and CH═CHCHR⁷ R⁸ ; R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7a), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl substituted with 0-2 R¹⁰ and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ; alternatively, R³ and R⁴ together form --OCH₂ O--; R⁵ is selected from H, F, Cl, Br, and I; alternatively, R⁴ and R⁵ together form --OCH₂ O-- or a fused benzo ring; R⁶ is selected from H, OH, C₁₋₃ alkoxy, --CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH₂ ; R⁷ is selected from H and C₁₋₃ alkyl; R^(7a) is selected from H and C₁₋₃ alkyl; R^(7b) is C₁₋₃ alkyl; R⁸ is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₆ alkenyl, C₃₋₇ cycloalkyl substituted with 0-2 R⁹, phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ; R⁹ is selected from ² H, OH, C₁₋₃ alkoxy, C₁₋₃ alkyl, and F; R¹⁰ is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷ R^(7a), and C (O)CH₃ ; R¹¹ is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷ R^(7a), CHO, C(O)CH₃, and C(O)NH₂ ; Q is selected from O, S and NH; and, p is selected from 0, 1, and
 2. 17. A method according to claim 16, wherein the reverse transcriptase inhibitor is selected from AZT, 3TC, rescriptor ddI, ddC, and d4T and the protease inhibitor is selected from saquinavir, ritonavir, nelfinavir, indinavir, VX-478, KNI-272, CGP-61755, and U-103017.
 18. A method according to claim 17, wherein the reverse transcriptase inhibitor is selected from AZT, rescriptor, and 3TC and the protease inhibitor is selected from saquinavir, ritonavir, nelfinavir, and indinavir.
 19. A method according to claim 18, wherein:R¹ is selected from CF₃, CF₂ H, C₂ F₅, C₁₋₃ alkyl, and C₃₋₅ cycloalkyl; and, R⁸ is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₆ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰.
 20. A method according to claim 19, wherein:R¹ is selected from CF₃, CF₂ H, C₂ F₅, C₂ H₅, isopropyl, and cyclopropyl; R³ is selected from H, F, Cl, Br, I, OCH₃, and CH₃ ; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7a), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; alternatively, R³ and R⁴ together form --OCH₂ O--; R⁵ is selected from H and F; R⁶ is selected from H, OH, OCH₃, --CN, F, CF₃, CH₃, and C(O)NH₂ ; R⁷ is selected from H and CH₃ ; R^(7a) is selected from H and CH₃ ; R^(7b) is CH₃ ; R⁸ is selected from H, C₁₋₄ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₄ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰ ; R⁹ is selected from ² H, OH, OCH₃, CH₃, and F; R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ; and, p is selected from 1 and
 2. 21. A method according to claim 20, wherein:A is O; R¹ is selected from CF₃, CF₂ H, and C₂ F₅ ; R² is selected from --OCHR⁷ R⁸, --OCH₂ C.tbd.C--R⁸, --OCH₂ C═C--R⁸, --OCH₂ CHR⁷ R⁸, --C.tbd.C--R⁸, --CH═CR⁷ R⁸, --CH₂ CHR⁷ R⁸, --CH₂ C.tbd.C--R⁸, CHR⁷ CH═CHR⁸, and CH═CHCHR⁷ R⁸ ; R³ is selected from H, F, Cl, Br, and I; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C.tbd.CH, OCH₃, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), C(O)OR⁷, NR⁷ SO₂ R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; alternatively, R³ and R⁴ together form --OCH₂ O--; and, R¹¹ is selected from OH, OCH₃, CN, F, Cl, NR⁷ R^(7a), C(O)CH₃, and C(O)NH₂.
 22. A method according to claim 16, wherein the compound is selected from:(±)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (-)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Cyclopropylethynyl-4-isopropyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Isopropylethynyl-4-trifluoromethyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Acetyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-(3-methyl)-1-buten-1-yl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Isopropylethynyl-4-trifluoromethyl-5,6-difluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Cyclopropylethynyl-6-chloro-4-trifluoromethyl-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(2-methoxyethoxy)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-propylamino-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(1-Butynyl)-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(1'-Hydroxy)-cyclopropylethynyl-4-trifluoromethyl-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(2-furanylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(2-pyridylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(cyclopropylethynyl)-8-methoxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(cyclopropylethynyl)-7-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(1-butynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(isopentyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-(1-propynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-pentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-isopentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Difluoro-4-butyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(2-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(2-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6-Methylenedioxy-4-(isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(1-propynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(2-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-butyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(phenylethyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Dimethylamino-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Dimethylamino-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Dimethylamino-4-pentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Dimethylamino-4-isopentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Acetyl-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6,8-Dichloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6,8-Dichloro-4-(phenylethyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6,8-Trifluoro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6,8-Trifluoro-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6,8-Trifluoro-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,6,8-Trifluoro-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,8-Difluoro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,8-Difluoro-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,8-Difluoro-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-5,8-Difluoro-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-(phenylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-pentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-(isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Isopropyl-4-(phenylethyl)-4-(trifluoro4 ethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluoromethoxy-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluoromethoxy-4-(isopropylethynyl)-4-(trifluoroethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluoromethoxy-4-(phenylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluoromethoxy-4-pentyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluororethoxy-4-(isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Trifluoromethoxy-4-(phenylethyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(Phenylethyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(Isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(Phenylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-4-(Pentyl)-4-(trifluoromethyl)-1,4-dihydro-2-3,1-benzoxazin-2-one; (±)-4-(Isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(isopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(1-pentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(4-methylpentynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(1-butynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Phenyl-4-(isopentyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(cyclopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(isopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(isopropylethynyl)-4-cyclopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(isopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(isopropylethynyl)-4-ethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methyl-4-(1-butynyl)-4-ethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6,7-Dichloro-4-(isopropylethynyl)-4-cyclopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6,7-Dichloro-4-(isopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-7-Chloro-4-(cyclopropylethynyl)-4-cyclopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-7-Chloro-4-(isopropylethynyl)-4-cyclopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-7-Chloro-4-(4-methylpentynyl)-4-cyclopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-7-Chloro-4-(cyclopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-7-Chloro-4-(isopropylethynyl)-4-isopropyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-8-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(isopropylethynyl)-4-(trifluoromethyl)-8-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Chloro-4-(phenylethyl)-4-(trifluoromethyl)-8-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one; (±)-6-Methoxy-4-(cyclopropylethynyl)-4-(trifluoromethyl)-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one; and, (±)-4-(Cyclopropylethynyl)-4-(trifluoromethyl)-6-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one. 